Data from FDA (Food and Drug Administration, USA) - Curated by Marshall Pearce - Last updated 10 October 2017

Indication(s)

INDICATIONS AND USAGE Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is indicated for the acute treatment of migraine headaches with or without aura. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is not intended for the prophylactic therapy of migraine or for the management of hemiplegic or basilar migraine.

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Advisory information

contraindications
CONTRAINDICATIONS 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, 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 WARNINGS) Because Migranal® (dihydroergotamine mesylate, USP) Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension. Migranal® (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. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be administered to patients with hemiplegic or basilar migraine. In addition to those conditions mentioned above, Migranal® (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. Migranal® (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 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, 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 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.
Special warnings and precautions
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). Drug Interactions Vasoconstrictors Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure. Sumatriptan Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Sumatriptan and Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be taken within 24 hours of each other. (See CONTRAINDICATIONS) Beta Blockers Although the results of a clinical study did not indicate a safety problem associated with the administration of Migranal® (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. Nicotine Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS. SSRI's Weakness, hyperreflexia, and incoordination have been reported rarely when 5HT1 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, USP) Nasal Spray or D.H.E. 45®. Oral Contraceptives The effect of oral contraceptives on the pharmacokinetics of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray has not been studied. 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.
Adverse reactions
ADVERSE REACTIONS During clinical studies and the foreign postmarketing experience with Migranal® (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 CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate (see WARNINGS: Fibrotic Complications). Incidence in Controlled Clinical Trials Of the 1,796 patients and subjects treated with Migranal® (dihydroergotamine mesylate, USP) 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, USP) 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, USP) 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, USP) 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, USP) 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% Other Adverse Events During Clinical Trials 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, USP) 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, USP) Nasal Spray in placebo-controlled trials and reported an event divided by the total number of patients (n=1796) exposed to Migranal® (dihydroergotamine mesylate, USP) 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. Skin and Appendages: Infrequent: petechia, pruritus, rash, cold clammy skin; Rare: papular rash, urticaria, herpes simplex. Musculoskeletal: Infrequent: cramps, myalgia, muscular weakness, dystonia; Rare: arthralgia, involuntary muscle contractions, rigidity. Central and Peripheral Nervous System: Infrequent: confusion, tremor, hypoesthesia, vertigo; Rare: speech disorder, hyperkinesia, stupor, abnormal gait, aggravated migraine. Autonomic Nervous System: Infrequent: increased sweating. Special Senses: Infrequent: sense of smell altered, photophobia, conjunctivitis, abnormal lacrimation, abnormal vision, tinnitus, earache; Rare: eye pain. Psychiatric: Infrequent: nervousness, euphoria, insomnia, concentration impaired; Rare: anxiety, anorexia, depression. Gastrointestinal: Infrequent: abdominal pain, dyspepsia, dysphagia, hiccup; Rare: increased salivation, esophagospasm. Cardiovascular: Infrequent: edema, palpitation, tachycardia; Rare: hypotension, peripheral ischemia, angina. Respiratory System: Infrequent: dyspnea, upper respiratory tract infections; Rare: bronchospasm, bronchitis, pleural pain, epistaxis. Urinary System: Infrequent: increased frequency of micturition, cystitis. Reproductive, Female: Rare: pelvic inflammation, vaginitis. Body as a Whole - General: Infrequent: feeling cold, malaise, rigors, fever, periorbital edema; Rare: flu-like symptoms, shock, loss of voice, yawning. Application Site: Infrequent: local anesthesia. Post-introduction Reports 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, USP) Nasal Spray is not recommended for prolonged daily use. (See DOSAGE AND ADMINISTRATION) To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC, at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION The solution used in Migranal® (dihydroergotamine mesylate, USP) Nasal Spray (4 mg/mL) is intended for intranasal use and must not be injected. In clinical trials, Migranal® (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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should be administered in each nostril. Fifteen minutes later, an additional one spray (0.5 mg) of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should be administered in each nostril, for a total dosage of four sprays (2.0 mg) of Migranal® (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. Migranal® (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. 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).
Pregnancy and lactation
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)

Interactions

Drug Interactions Vasoconstrictors Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure. Sumatriptan Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Sumatriptan and Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be taken within 24 hours of each other. (See CONTRAINDICATIONS) Beta Blockers Although the results of a clinical study did not indicate a safety problem associated with the administration of Migranal® (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. Nicotine Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS. SSRI's Weakness, hyperreflexia, and incoordination have been reported rarely when 5HT1 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, USP) Nasal Spray or D.H.E. 45®. Oral Contraceptives The effect of oral contraceptives on the pharmacokinetics of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray has not been studied.

More information

Category Value
Authorisation number NDA020148
Agency product number 81AXN7R2QT
Orphan designation No
Product NDC 0187-0245
Date Last Revised 16-08-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 861670
Storage and handling Store below 25°C (77°F). Do not refrigerate or freeze.
Marketing authorisation holder Valeant Pharmaceuticals North America LLC
Warnings WARNING Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 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 also CONTRAINDICATIONS and WARNINGS section)