Migranal (Dihydroergotamine Mesylate)

MIGRANAL®

Novartis Pharmaceuticals

Dihydroergotamine Mesylate

Migraine Therapy

Action And Clinical Pharmacology: Dihydroergotamine displays agonist activity at the 5-HT1D receptor, which, by reducing 5-HT neuronal function and/or contracting elements of the cranial vasculature and/or suppressing neurogenic inflammation, is believed to underlie its antimigraine efficacy. It also displays affinity for the 5-HT1C receptor and antagonistic activity at the 5-HT2 subtype. Dihydroergotamine displays blocking actions at alpha adrenoreceptors, with a direct stimulating effect on the smooth muscle of peripheral blood vessels. Its tonic effect on capacitance vessels (veins) is particularly pronounced, compared to its effects on resistance vessels (arterioles). Dihydroergotamine differs from ergotamine by being more potent with respect to its adrenergic blocking actions and less potent with respect to its capacity to produce arterial vasoconstriction, but it maintains a marked venoconstrictor effect. Dihydroergotamine reduces the incidence and degree of nausea, photophobia, and phonophobia.

Intranasally administered dihydroergotamine is rapidly absorbed in a dose-independent manner (tmax=approximately 45 minutes). Significant relief of migraine begins within approximately 30 minutes following administration of dihydroergotamine nasal spray. Once pain is relieved, the incidence of return of pain within 24 hours is low. The bioavailability of dihydroergotamine administered intranasally is 43%.

Dihydroergotamine is 93% bound to plasma proteins and has a steady-state volume of distribution of about 800 L. The parent drug constitutes 70 to 80% of plasma concentrations of drug-related materials. The nasal spray form of dihydroergotamine, like most parenteral dose routes, is not subject to first-pass hepatic metabolism. The total body clearance is about 1.5 L/min, reflecting mainly a hepatic clearance. Plasma elimination of dihydroergotamine is biphasic with a mean terminal half-life of 10 hours. The major route of excretion is via the bile in the feces. After intranasal administration, the urinary recovery of parent drug amounts to about 2% of the dose.

Indications And Clinical Uses: For the treatment of migraine headaches, with or without aura in adults.

Dihydroergotamine nasal spray is not indicated for prophylactic therapy or for the management of hemiplegic or basilar migraine.

Contra-Indications: Patients who have previously shown hypersensitivity to ergot alkaloids, or to any of the components of dihydroergotamine nasal spray.

Dihydroergotamine nasal spray is contraindicated in patients having conditions predisposing to vasospastic reactions such as known peripheral arterial disease, coronary heart disease (in particular unstable or vasospastic angina), septic conditions and shock, vascular surgery, obliterative vascular disease, inadequately controlled hypertension, and severely impaired hepatic function.

Pregnancy and Lactation: Dihydroergotamine possesses oxytocic properties and, therefore, should not be administered during pregnancy. It is likely that dihydroergotamine is excreted in breast milk. Dihydroergotamine nasal spray is therefore contraindicated for nursing mothers.

Manufacturers’ Warnings In Clinical States: Dihydroergotamine could cause vasospastic reactions, including angina, although it seems to do so less frequently than ergotamine. This action appears to be dose-related. These reactions are manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia (e.g., muscle pains, numbness, coldness and pallor or cyanosis of the digits), angina or unusual syndromes, such as mesenteric ischemia. Consequently, dihydroergotamine nasal spray should be discontinued immediately if signs or symptoms of vasoconstriction develop.

The solution used in Migranal was especially developed for intranasal administration and must not be injected.

Precautions: Children: Safety and effectiveness of dihydroergotamine nasal spray in children have not been established.

Geriatrics: Experience with the use of dihydroergotamine nasal spray in patients aged over 65 years is limited.

Drug Interactions: The concomitant use of oral contraceptives by female patients does not appear to influence the disposition of dihydroergotamine nasal spray.

Dihydroergotamine nasal spray should not be used with vasoconstrictors because the combination may cause a further elevation of blood pressure.

Concurrent use of vasoconstrictor agents including ergotamine, sumatriptan and nicotine may enhance the risk of vasoconstriction. Twenty four hours should elapse before taking sumatriptan following administration of dihydroergotamine nasal spray. This will avoid additive vasospastic effects. Conversely, dihydroergotamine nasal spray can be taken 6 hours following the administration of sumatriptan.

Although there have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by synergism upon b-blockade, the results of a limited clinical study (n=8) did not indicate a safety problem associated with the administration of dihydroergotamine nasal spray in subjects already receiving propranolol.

The concomitant use of macrolide antibiotics such as erythromycin, troleandomycin or josamycin with dihydroergotamine nasal spray should be avoided since these antibiotics may increase the plasma level of dihydroergotamine.

Lactation: It is likely that dihydroergotamine is excreted in human milk, although it is not known at which concentration, while it is known that ergotamine is excreted in breast milk and may cause vomiting, diarrhea, weak pulse and unstable blood pressure in breast-fed infants. Because of the potential for these serious adverse events in breast-fed infants, nursing mothers should not use dihydroergotamine nasal spray.

Information for the Patient: Currently available data have not demonstrated drug abuse and psychological dependence with dihydroergotamine nasal spray. However, due to the chronicity of migraines, patients should be advised not to exceed recommended dosages.

Patients should be advised to report immediately to the physician 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.

Patients should be advised of the importance of priming the applicator (pump 4 times) prior to administration to ensure correct dosage. No more than 4 sprays should be administered for any single migraine headache attack. No more than 8 sprays should be administered during any 24 hour period. The maximum weekly dosage is 24 sprays (see Dosage).

Adverse Reactions: The most commonly reported adverse events associated with the use of dihydroergotamine nasal spray in placebo-controlled, double-blind studies for the treatment of migraine headaches, and not reported at an equivalent incidence by placebo-treated patients, were rhinitis (which includes reports of all nasal-related adverse reactions), nausea, taste disturbance and application site reaction. In clinical trials these events were transient and self-limiting, and generally did not result in patient drop-out. Table I lists the adverse events experienced at incidences greater than 1%.

In a few patients who have taken oral dihydroergotamine continuously over years, development of fibrotic changes, in particular of the pleura and the retroperitoneum, has been observed.

Chest tightness/pain was seen in earlier studies although the incidence was less than 1%, and a causal relationship was not established.

In rare cases, vascular spasms may occur, particularly in the lower extremities. If signs of vascular spasms are observed, dihydroergotamine nasal spray should be discontinued and treatment with a peripheral vasodilator initiated (see Overdose: Symptoms and Treatment).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of acute overdosage with dihydroergotamine nasal spray. The symptoms of an acute oral dihydroergotamine overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with dihydroergotamine. These symptoms include the following: peripheral signs and symptoms of vasospasm (e.g., 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.

The treatment of an overdosage is symptomatic under close monitoring of the cardiovascular and respiratory systems. Treatment includes discontinuation of the drug, local application of warmth to the affected area and nursing care to prevent tissue damage; in case of severe vasospasms, vasodilators should be administered (e.g., sodium nitroprusside, phentolamine or dihydralazine). In the case of coronary constriction, appropriate treatment such as nitroglycerin should be initiated.

Dosage And Administration: Prior to administration of dihydroergotamine nasal spray the sprayer must be primed (pumped 4 times in the air) (See Blue Section – Information for the Patient “Migranal”).

For best results, treatment should be initiated at the first symptom or sign of an attack. However, dihydroergotamine nasal spray can be used at any stage of a migraine attack.

The usual dosage required to obtain optimal efficacy and lasting relief is a total dosage of four sprays (corresponding to 1 bottle) of dihydroergotamine nasal spray. At the first sign or symptoms of a migraine headache, or as early as possible after the onset of headache pain, 1 spray of dihydroergotamine nasal spray should be administered into each nostril (total of 2 sprays). If the condition has not sufficiently improved approximately 15 minutes later, or to obtain optimal efficacy, an additional spray of dihydroergotamine nasal spray should be administered to each nostril (total of additional 2 sprays). Once the sprayer has been prepared, it must be discarded with any remaining drug after 8 hours.

In order to let the drug be absorbed through the skin in the nose, patients should not inhale deeply through the nose while spraying or immediately after spraying.

Dihydroergotamine nasal spray is exclusively indicated for the symptomatic treatment of migraine attacks. Dihydroergotamine nasal spray should not be used as a prophylactic therapy.

Significant relief of migraine begins within approximately 30 minutes following nasal administration of dihydroergotamine nasal spray.

No more than 1 bottle (4 sprays) should be administered for any single migraine attack. An interval of at least 6 to 8 hours should be observed before treating another migraine attack with dihydroergotamine nasal spray or any drug containing dihydroergotamine or ergotamine. No more than 2 bottles (8 sprays) should be administered during any 24-hour period. The maximum weekly dosage is 6 bottles (24 sprays) of dihydroergotamine nasal spray. Once pain is relieved, the incidence of pain return within 24 hours (migraine recurrence) is low.

Dihydroergotamine nasal spray does not need to be administered with an antiemetic, as is recommended with the parenteral form of dihydroergotamine mesylate, since the administration of the nasal spray form is not associated with nausea and vomiting to the same extent as the parenteral form.

Availability And Storage: Each mL of clear, colorless to faintly yellow solution contains: dihydroergotamine mesylate USP 4 mg. Nonmedicinal ingredients: anhydrous caffeine, anhydrous dextrose, carbon dioxide and water. Packages of 3 units, each unit consisting of 1 bottle and a sprayer. Store at room temperature (15 to 25°C).

MIGRANAL® Novartis Pharmaceuticals Dihydroergotamine Mesylate Migraine Therapy

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