Source: FDA, National Drug Code (US) Revision Year: 2019
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 WARNINGS: CYP 3A4 Inhibitors).
MIGRANAL (dihydroergotamine mesylate) 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 WARNINGS).
Because MIGRANAL (dihydroergotamine mesylate) Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension.
MIGRANAL (dihydroergotamine mesylate) 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.
MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be administered to patients with hemiplegic or basilar migraine.
In addition to those conditions mentioned above, MIGRANAL (dihydroergotamine mesylate) Nasal Spray is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery, and severely impaired hepatic or renal function.
MIGRANAL (dihydroergotamine mesylate) 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 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 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.
MIGRANAL (dihydroergotamine mesylate) Nasal Spray 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.
MIGRANAL (dihydroergotamine mesylate) Nasal Spray 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 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 CYP 3A4 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 MIGRANAL (dihydroergotamine mesylate) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).
MIGRANAL (dihydroergotamine mesylate) 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) 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) 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) 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) Nasal Spray, in these patients with risk factors.
It is recommended that patients who are intermittent long-term users of MIGRANAL (dihydroergotamine mesylate) 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) Nasal Spray.
The systematic approach described above is currently recommended as a method to identify patients in whom MIGRANAL (dihydroergotamine mesylate) Nasal Spray may be used to treat migraine headaches with an acceptable margin of cardiovascular safety.
No deaths have been reported in patients using MIGRANAL (dihydroergotamine mesylate) 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.
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).
MIGRANAL (dihydroergotamine mesylate) 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) Nasal Spray.
MIGRANAL (dihydroergotamine mesylate) 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) Nasal Spray should be discontinued immediately if signs or symptoms of vasoconstriction develop.
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) Nasal Spray and dihydroergotamine mesylate injection. MIGRANAL (dihydroergotamine mesylate) 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.
Approximately 30% of patients using MIGRANAL (dihydroergotamine mesylate) 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) 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) 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.
During clinical studies and the foreign postmarketing experience with MIGRANAL (dihydroergotamine mesylate) 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 CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).
Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate (see WARNINGS: Fibrotic Complications).
Of the 1,796 patients and subjects treated with MIGRANAL (dihydroergotamine mesylate) Nasal Spray doses 2 mg or less in U.S. and foreign clinical studies, 26 (1.4%) discontinued because of adverse events. The adverse events associated with discontinuation were, in decreasing order of frequency: rhinitis 13, dizziness 2, facial edema 2, and one each due to cold sweats, accidental trauma, depression, elective surgery, somnolence, allergy, vomiting, hypotension, and paraesthesia.
The most commonly reported adverse events associated with the use of MIGRANAL (dihydroergotamine mesylate) Nasal Spray during placebo-controlled, double-blind studies for the treatment of migraine headache and not reported at an equal incidence by placebo-treated patients were rhinitis, altered sense of taste, application site reactions, dizziness, nausea, and vomiting. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.
MIGRANAL (dihydroergotamine mesylate) Nasal Spray was generally well tolerated. In most instances these events were transient and self-limited and did not result in patient discontinuation from a study. The following table summarizes the incidence rates of adverse events reported by at least 1% of patients who received MIGRANAL (dihydroergotamine mesylate) Nasal Spray for the treatment of migraine headaches during placebo-controlled, double-blind clinical studies and were more frequent than in those patients receiving placebo.
Table 3. Adverse events reported by at least 1% of the MIGRANAL (dihydroergotamine mesylate) Nasal Spray treated patients and occurred more frequently than in the placebo-group in the migraine placebo-controlled trials:
| MIGRANAL N=597 | Placebo N=631 | |
|---|---|---|
| Respiratory System | ||
| Rhinitis | 26% | 7% |
| Pharyngitis | 3% | 1% |
| Sinusitis | 1% | 1% |
| Gastrointestinal System | ||
| Nausea | 10% | 4% |
| Vomiting | 4% | 1% |
| Diarrhea | 2% | <1% |
| Special Senses, Other | ||
| Altered Sense of Taste | 8% | 1% |
| Application Site | ||
| Application Site Reaction | 6% | 2% |
| Central and Peripheral Nervous System | ||
| Dizziness | 4% | 2% |
| Somnolence | 3% | 2% |
| Paraesthesia | 2% | 2% |
| Body as a Whole, General | ||
| Hot Flashes | 1% | <1% |
| Fatigue | 1% | 1% |
| Asthenia | 1% | 0% |
| Autonomic Nervous System | ||
| Mouth Dry | 1% | 1% |
| Musculoskeletal System | ||
| Stiffness | 1% | <1% |
In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of MIGRANAL (dihydroergotamine mesylate) Nasal Spray in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used MIGRANAL (dihydroergotamine mesylate) Nasal Spray in placebo-controlled trials and reported an event divided by the total number of patients (n=1796) exposed to MIGRANAL (dihydroergotamine mesylate) Nasal Spray. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; and rare adverse events are those occurring in fewer than 1/1,000 patients.
Infrequent: petechia, pruritus, rash, cold clammy skin.
Rare: papular rash, urticaria, herpes simplex.
Infrequent: cramps, myalgia, muscular weakness, dystonia.
Rare: arthralgia, involuntary muscle contractions, rigidity.
Infrequent: confusion, tremor, hypoesthesia, vertigo.
Rare: speech disorder, hyperkinesia, stupor, abnormal gait, aggravated migraine.
Infrequent: increased sweating.
Infrequent: sense of smell altered, photophobia, conjunctivitis, abnormal lacrimation, abnormal vision, tinnitus, earache.
Rare: eye pain.
Infrequent: nervousness, euphoria, insomnia, concentration impaired.
Rare: anxiety, anorexia, depression.
Infrequent: abdominal pain, dyspepsia, dysphagia, hiccup.
Rare: increased salivation, esophagospasm.
Infrequent: edema, palpitation, tachycardia.
Rare: hypotension, peripheral ischemia, angina.
Infrequent: dyspnea, upper respiratory tract infections.
Rare: bronchospasm, bronchitis, pleural pain, epistaxis.
Infrequent: increased frequency of micturition, cystitis.
Rare: pelvic inflammation, vaginitis.
Infrequent: feeling cold, malaise, rigors, fever, periorbital edema.
Rare: flu-like symptoms, shock, loss of voice, yawning.
Infrequent: local anesthesia.
Voluntary reports of adverse events temporally associated with dihydroergotamine products used in the management of migraine that have been received since the introduction of the injectable formulation are included in this section save for those already listed above. Because of their source (open and uncontrolled clinical use), whether or not events reported in association with the use of dihydroergotamine are causally related to it cannot be determined. There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of injectable dihydroergotamine mesylate. MIGRANAL (dihydroergotamine mesylate) Nasal Spray is not recommended for prolonged daily use (See DOSAGE AND ADMINISTRATION).
MIGRANAL (dihydroergotamine mesylate) 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).
see WARNINGS: Fibrotic Complications
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) 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) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).
MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure.
Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Sumatriptan and MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be taken within 24 hours of each other (See CONTRAINDICATIONS).
Although the results of a clinical study did not indicate a safety problem associated with the administration of MIGRANAL (dihydroergotamine mesylate) 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.
Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy.
See CONTRAINDICATIONS and WARNINGS.
Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT1 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 MIGRANAL (dihydroergotamine mesylate) Nasal Spray or D.H.E. 45.
The effect of oral contraceptives on the pharmacokinetics of MIGRANAL (dihydroergotamine mesylate) Nasal Spray has not been studied.
See CONTRAINDICATIONS.
Ergot drugs are known to inhibit prolactin. It is likely that MIGRANAL (dihydroergotamine mesylate) 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) Nasal Spray, nursing should not be undertaken with the use of MIGRANAL (dihydroergotamine mesylate) Nasal Spray (See CONTRAINDICATIONS).
Safety and effectiveness in pediatric patients have not been established.
There is no information about the safety and effectiveness of MIGRANAL (dihydroergotamine mesylate) Nasal Spray in this population because patients over age 65 were excluded from the controlled clinical trials.
Currently available data have not demonstrated drug abuse or psychological dependence with dihydroergotamine. However, cases of drug abuse and psychological dependence in patients on other forms of ergot therapy have been reported. Thus, due to the chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages.
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