DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 1 mL ampul Carton. NDC 66490-041-01Rx OnlyD.H.E. 45(dihydroergotamine mesylate) injection, USP1 mg/mL (1 mL ampul)FOR INTRAVENOUS, INTRAMUSCULAR,AND SUBCUTANEOUS USE ONLY10 1 mL ampulsUnit Dose PackageBausch Health DHE 45 1MG CARTON.

PEDIATRIC USE SECTION.

Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Serious cardiac events, including some that have been fatal, have occurred following use of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, 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 ).. Post-introduction Reports. The following events derived from postmarketing experience have been occasionally reported in patients receiving D.H.E. 45 (dihydroergotamine mesylate) Injection, USP: 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. causal relationship has not been established.D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is not recommended for prolonged daily use (see DOSAGE AND ADMINISTRATION ).To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BOXED WARNING SECTION.

WARNING. Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of dihydroergotamine with potent CYP3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP3A4 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 CONTRAINDICATIONS and WARNINGS).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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. Impairment of fertility was not evaluated for D.H.E. 45 (dihydroergotamine mesylate) Injection, USP. There was no evidence of impairment of fertility in rats given intranasal doses of MigranaL(R) Nasal Spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately to 11 times those in humans receiving the MRDD of mg).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. Dihydroergotamine binds with high affinity to 5-HT1D and 5-HT1D receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline 2A, 2B and receptors, and dopamine D2L and D3 receptors.The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine. One theory suggests that activation of 5-HT1D receptors located on intracranial blood vessels, including those on arteriovenous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.In addition, dihydroergotamine possesses oxytocic properties (see CONTRAINDICATIONS ).. Pharmacokinetics. Absorption. Absolute bioavailability for the subcutaneous and intramuscular route have not been determined; however, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses.Dihydroergotamine mesylate is poorly bioavailable following oral administration.. Distribution. Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.. Metabolism. Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8--hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, (i.e., dihydrolysergic acid, dihydrolysergic amide) and metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20% to 30% of plasma AUC. Quantitative pharmacokinetic characterization of the four metabolites has not been performed.. Excretion. The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. Only 6% to 7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with terminal half-life of about hours.. Subpopulations. No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is contraindicated in patients with severely impaired hepatic or renal function (see CONTRAINDICATIONS ).. Interactions. Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P4503A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P4503A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g., ritonavir), presumably due to inhibition of cytochrome P4503A metabolism of ergotamine (see CONTRAINDICATIONS ). No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. There have been few reports of serious adverse events associated with the coadministration of dihydroergotamine and potent CYP3A4 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 CYP3A4 inhibitors (i.e., ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole) with dihydroergotamine is, therefore, contraindicated (see WARNINGS, CYP3A4 Inhibitors ).D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be given to patients with ischemic heart disease (e.g., 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 Prinzmetals variant angina (see WARNINGS ).Because D.H.E. 45 (dihydroergotamine mesylate) Injection, USP may increase blood pressure, it should not be given to patients with uncontrolled hypertension.D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other.D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be administered to patients with hemiplegic or basilar migraine.In addition to those conditions mentioned above, D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery and severely impaired hepatic or renal function.D.H.E. 45 (dihydroergotamine mesylate) Injection, USP may cause fetal harm when administered to 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 to 1.2 times the exposures in humans receiving the MRDD of mg) or greater. no effect level for embryofetal 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 times human exposures at the MRDD) during organogenesis. 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. 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.D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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.

DESCRIPTION SECTION.

DESCRIPTION. D.H.E. 45 is ergotamine hydrogenated in the 9, 10 position as the mesylate salt. D.H.E. 45 is known chemically as ergotaman-3,6,18-trione,9,10-dihydro-12-hydroxy-2-methyl-5-(phenylmethyl)-,(5)-, monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is C33H37N5O5oCH4O3S.The chemical structure is:Dihydroergotamine mesylateC33H37N5O5oCH4O3S Mol. Wt. 679.80D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is clear, colorless solution supplied in sterile ampuls for intravenous, intramuscular, or subcutaneous administration. Each mL contains mg Dihydroergotamine Mesylate, USP; Alcohol, USP 6.1% by volume; Glycerin, USP 15% by weight; Water for Injection, USP; Methanesulfonic Acid and/or Sodium Hydroxide for pH adjustment (pH range is 3.4 to 4.9).. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should be administered in dose of mL intravenously, intramuscularly or subcutaneously. The dose can be repeated, as needed, at 1-hour intervals to total dose of mL for intramuscular or subcutaneous delivery or mL for intravenous delivery in 24-hour period. The total weekly dosage should not exceed mL. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be used for chronic daily administration.

DRUG INTERACTIONS SECTION.

Drug Interactions. Vasoconstrictors. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 D.H.E. 45(dihydroergotamine mesylate) Injection, USP. Sumatriptan and D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be taken within 24 hours of each other (see CONTRAINDICATIONS ).. Beta Blockers. Although the results of clinical study did not indicate safety problem associated with the administration of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 greater ischemic response to ergot therapy.. CYP3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors) (see CONTRAINDICATIONS and WARNINGS) SSRIs. Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT1 agonists have been co-administered with SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRIs and D.H.E. 45(dihydroergotamine mesylate) Injection, USP.. Oral Contraceptives. The effect of oral contraceptives on the pharmacokinetics of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP has not been studied.

GENERAL PRECAUTIONS SECTION.

General. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 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 Raynauds syndrome following the use of any 5-HT agonist are candidates for further evaluation (see WARNINGS).

HOW SUPPLIED SECTION.

HOW SUPPLIED/STORAGE AND HANDLING. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP. Available as clear, colorless, sterile solution in single mL sterile ampuls containing mg of dihydroergotamine mesylate per mL, in packages of 10 (NDC 66490-041-01).. Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [see USPControlled Room Temperature]. Use carton to protect contents from light until used.Do not refrigerate or freeze.To assure constant potency, protect the ampuls from light and heat. Administer only if clear and colorless.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is indicated for the acute treatment of migraine headaches with or without aura and the acute treatment of cluster headache episodes.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. The text of patient information sheet is printed at the end of this insert. To assure safe and effective use of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, the information and instructions provided in the patient information sheet should be discussed with patients.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 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION ).

MECHANISM OF ACTION SECTION.

Mechanism of Action. Dihydroergotamine binds with high affinity to 5-HT1D and 5-HT1D receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline 2A, 2B and receptors, and dopamine D2L and D3 receptors.The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine. One theory suggests that activation of 5-HT1D receptors located on intracranial blood vessels, including those on arteriovenous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.In addition, dihydroergotamine possesses oxytocic properties (see CONTRAINDICATIONS ).

NURSING MOTHERS SECTION.

Nursing Mothers. Ergot drugs are known to inhibit prolactin. It is likely that D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, nursing should not be undertaken with the use of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP (see CONTRAINDICATIONS ).

OVERDOSAGE SECTION.

OVERDOSAGE. 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 D.H.E. 45(dihydroergotamine mesylate) Injection, USP 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with D.H.E. 45(dihydroergotamine mesylate) Injection, USP. 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 certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians Desk Reference (PDR).

PHARMACOKINETICS SECTION.

Pharmacokinetics. Absorption. Absolute bioavailability for the subcutaneous and intramuscular route have not been determined; however, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses.Dihydroergotamine mesylate is poorly bioavailable following oral administration.. Distribution. Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.. Metabolism. Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8--hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, (i.e., dihydrolysergic acid, dihydrolysergic amide) and metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20% to 30% of plasma AUC. Quantitative pharmacokinetic characterization of the four metabolites has not been performed.. Excretion. The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. Only 6% to 7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with terminal half-life of about hours.. Subpopulations. No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is contraindicated in patients with severely impaired hepatic or renal function (see CONTRAINDICATIONS ).. Interactions. Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P4503A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P4503A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g., ritonavir), presumably due to inhibition of cytochrome P4503A metabolism of ergotamine (see CONTRAINDICATIONS ). No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

PRECAUTIONS SECTION.

PRECAUTIONS. General. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 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 Raynauds syndrome following the use of any 5-HT agonist are candidates for further evaluation (see WARNINGS).. Information for Patients. The text of patient information sheet is printed at the end of this insert. To assure safe and effective use of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, the information and instructions provided in the patient information sheet should be discussed with patients.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 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION ).. Drug Interactions. Vasoconstrictors. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 D.H.E. 45(dihydroergotamine mesylate) Injection, USP. Sumatriptan and D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be taken within 24 hours of each other (see CONTRAINDICATIONS ).. Beta Blockers. Although the results of clinical study did not indicate safety problem associated with the administration of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 greater ischemic response to ergot therapy.. CYP3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors) (see CONTRAINDICATIONS and WARNINGS) SSRIs. Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT1 agonists have been co-administered with SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRIs and D.H.E. 45(dihydroergotamine mesylate) Injection, USP.. Oral Contraceptives. The effect of oral contraceptives on the pharmacokinetics of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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. Impairment of fertility was not evaluated for D.H.E. 45 (dihydroergotamine mesylate) Injection, USP. There was no evidence of impairment of fertility in rats given intranasal doses of MigranaL(R) Nasal Spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately to 11 times those in humans receiving the MRDD of mg).. Pregnancy. Nursing Mothers. Ergot drugs are known to inhibit prolactin. It is likely that D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, nursing should not be undertaken with the use of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP (see CONTRAINDICATIONS ).. Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

SPL PATIENT PACKAGE INSERT SECTION.

INSTRUCTION FOR PATIENTS ON SUBCUTANEOUS SELF-INJECTION. Information for the PatientD.H.E. 45 (dihydroergotamine mesylate) Injection, USPBefore self-injecting D.H.E. 45 (dihydroergotamine mesylate) Injection, USP by subcutaneous administration, you will need to obtain professional instruction on how to properly administer your medication. Below are some of the steps you should follow carefully. Read this leaflet completely before using this medication.This leaflet does not contain all of the information on D.H.E. 45 (dihydroergotamine mesylate) Injection, USP. Your pharmacist and/or health care provider can provide more detailed information.Purpose of your medicationD.H.E. 45 (dihydroergotamine mesylate) Injection, USP is intended to treat an active migraine headache. Do not try to use it to prevent headache if you have no symptoms. Do not use it to treat common tension headache or headache that is not at all typical of your usual migraine headache. Administration of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not exceed the dosing guidelines and should not be used for chronic daily administration. There have been reports of fibrosis (stiffening) in the lung or kidney areas in patients following prolonged daily use of injectable dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs (the class of drugs to which D.H.E. 45 (dihydroergotamine mesylate) Injection, USP belongs) has been associated with heart 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 heart valvular fibrosis.Do not use D.H.E. 45 (dihydroergotamine mesylate) Injection, USP if you:oare pregnant or nursing.ohave any disease affecting your heart, arteries, or circulation.oare taking certain anti-HIV medications (protease inhibitors).oare taking macrolide antibiotic such as troleandomycin, clarithromycin or erythromycin.Important questions to consider before using D.H.E. 45 (dihydroergotamine mesylate) Injection, USPPlease answer the following questions before you use your D.H.E. 45 (dihydroergotamine mesylate) Injection, USP.If you answer YES to any of these questions or are unsure of the answer, you should talk to your doctor before using D.H.E. 45 (dihydroergotamine mesylate) Injection, USP.oDo you have high blood pressureoDo you have chest pain, shortness of breath, heart disease, or have you had any surgery on your heart arteriesoDo you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal or male over 40)oDo you have any problems with blood circulation in your arms or legs, fingers, or toesoAre you pregnant Do you think you might be pregnant Are you trying to become pregnant Are you sexually active and not using birth control Are you breastfeedingoHave you ever had to stop taking this or any other medication because of an allergy or bad reactionoAre you taking any other migraine medications, erythromycin or other antibiotics, or medications for blood pressure prescribed by your doctor, or other medicines obtained from your drugstore without doctors prescriptionoDo you smokeoHave you had, or do you have, any disease of the liver or kidneyoIs this headache different from your usual migraine attacksoAre you using D.H.E. 45 (dihydroergotamine mesylate) Injection, USP nasal spray or other dihydroergotamine mesylate containing drugs on daily basisoAre you taking protease inhibitor for HIV therapyoAre you taking macrolide class of antibioticSerious or potentially life-threatening reductions in blood flow to the brain or extremities have been reported rarely due to interactions between D.H.E. 45 (dihydroergotamine mesylate) Injection, USP and protease inhibitors or macrolide antibiotics.REMEMBER TO TELL YOUR DOCTOR IF YOU HAVE ANSWERED YES TO ANY OF THESE QUESTIONS BEFORE YOU USE D.H.E. 45 (dihydroergotamine mesylate) Injection, USPSide effects to watch out forAlthough the following reactions rarely occur, they can be serious and should be reported to your physician immediately:oNumbness or tingling in your fingers and toesoPain, tightness, or discomfort in your chestoMuscle pain or cramps in your arms and legsoWeakness in your legsoTemporary speeding or slowing of your heart rateoSwelling or itchingDosageYour doctor will have told you what dose to use for each migraine attack. Should you get another migraine attack in the same day as the attack you treated, you must not treat it with D.H.E. 45 (dihydroergotamine mesylate) Injection, USP unless at least hours have elapsed since your last injection. No more than mL of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should be injected during 1-week period. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is not intended to be used on prolonged daily basis.Learn what to do in case of an OverdoseIf you have used more medication than you have been instructed, contact your doctor, hospital emergency department, or nearest poison control center immediately.How to use the D.H.E. 45 (dihydroergotamine mesylate) Injection, USP1.Use Available Training MaterialsoRead and follow the instructions in the patient instruction booklet which is provided with the D.H.E. 45 (dihydroergotamine mesylate) Injection, USP package before attempting to use the product.oIf there are any questions concerning the use of your D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, ask your doctor or pharmacist.2.Preparing for the InjectionoCarefully examine the ampul (glass vial) of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP for any cracks or breaks, and the liquid for discoloration, cloudiness, or particles. If any of these defects are present, use new ampul, make certain it is intact, and return the defective ampul to your doctor or pharmacy. Once you open an ampul, if it is not used within an hour, it should be thrown away.3.Locating an Injection SiteoAdminister your subcutaneous injection in the middle of your thigh, well above the knee.4.Drawing the Medication into the Syringea.Wash your hands thoroughly with soap and water.b. Check the dose of your medication.c.Look to see if there is any liquid at the top of the ampul. If there is, gently flick the ampul with your finger to get all the liquid into the bottom portion of the ampul.d.Hold the bottom of the ampul in one hand. Clean the ampul neck with an alcohol wipe using the other hand. To break, place the alcohol wipe around the neck of the ampul and break it open by pressing your thumb against the neck of the ampul.e.Tilt the ampul down at 45 angle. Insert the needle into the solution in the ampul.f.Draw up the medication by pulling back the plunger slowly and steadily until you reach your dose.g.Check the syringe for air bubbles. Hold it with the needle pointing upward. If there are air bubbles, tap your finger against the barrel of the syringe to get the bubbles to the top. Slowly and carefully push the plunger up so that the bubbles are pushed out through the needle and you see drop of medication.h.When there are no air bubbles, check the dose of the medication. If the dose is incorrect, repeat steps e, f, g, and until you draw up the right dose.5.Preparing the Injection SiteoWith new alcohol wipe, clean the selected injection site thoroughly with firm, circular motion from inside to outside. Wait for the injection site to dry before injecting.6.Administering the InjectionoHold the syringe/needle in your right hand.oWith your left hand, firmly grasp about 1-inch fold of skin at the injection site.oPush the needle shaft, bevel side up, all the way into the fold of skin at 45 to 90 angle, then release the fold of skin.oWhile holding the syringe with your left hand, use your right hand to draw back slightly on the plunger.oIf you do not see any blood coming back into the syringe, inject the medication by pushing down on the plunger. If you do see blood in the syringe, that means the needle has penetrated vein. If this happens, pull the needle/syringe out of the skin slightly and draw back on the plunger again. If no blood is seen this time, inject the medication.oUse your right hand to pull the needle out of your skin quickly at the same angle you injected it. Immediately press the alcohol wipe on the injection site and rub.Check the expiration date printed on the ampul containing medication. If the expiration date has passed, do not use it.Answers to Patients Questions About D.H.E. 45 (dihydroergotamine mesylate) Injection, USPWhat if need help in using my D.H.E. 45 (dihydroergotamine mesylate) Injection, USPIf you have any questions or if you need help in opening, putting together, or using D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, speak to your doctor or pharmacist.How much medication should use and how oftenYour doctor will have told you what dose to use for each migraine attack. Should you get another migraine attack in the same day as the attack you treated, you must not treat it with D.H.E. 45 (dihydroergotamine mesylate) Injection, USP unless at least hours have elapsed since your last injection. No more than mL of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should be injected during 1-week period. Do not use more than this amount unless instructed to do so by your doctor. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is not intended for chronic daily use.If you have any other unanswered questions about D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, consult your doctor or pharmacist.Trademark of PDR Network, LLCDistributed by:Bausch Health US, LLCBridgewater, NJ 08807 USAManufactured by:Jubilant HollisterStier General Partnership 16751 Trans-Canada HighwayKirkland, Quebec H9H 4J4, Canada(R)/(TM) are trademarks of Bausch Health Companies Inc. or its affiliates.(C) 2019 Bausch Health Companies Inc. or its affiliates Rev. 11/19 9614601 6W500 9L J2. oare pregnant or nursing.. ohave any disease affecting your heart, arteries, or circulation.. oare taking certain anti-HIV medications (protease inhibitors).. oare taking macrolide antibiotic such as troleandomycin, clarithromycin or erythromycin.. oDo you have high blood pressure. oDo you have chest pain, shortness of breath, heart disease, or have you had any surgery on your heart arteries. oDo you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal or male over 40). oDo you have any problems with blood circulation in your arms or legs, fingers, or toes. oAre you pregnant Do you think you might be pregnant Are you trying to become pregnant Are you sexually active and not using birth control Are you breastfeeding. oHave you ever had to stop taking this or any other medication because of an allergy or bad reaction. oAre you taking any other migraine medications, erythromycin or other antibiotics, or medications for blood pressure prescribed by your doctor, or other medicines obtained from your drugstore without doctors prescription. oDo you smoke. oHave you had, or do you have, any disease of the liver or kidney. oIs this headache different from your usual migraine attacks. oAre you using D.H.E. 45 (dihydroergotamine mesylate) Injection, USP nasal spray or other dihydroergotamine mesylate containing drugs on daily basis. oAre you taking protease inhibitor for HIV therapy. oAre you taking macrolide class of antibiotic. oNumbness or tingling in your fingers and toes. oPain, tightness, or discomfort in your chest. oMuscle pain or cramps in your arms and legs. oWeakness in your legs. oTemporary speeding or slowing of your heart rate. oSwelling or itching. 1.Use Available Training MaterialsoRead and follow the instructions in the patient instruction booklet which is provided with the D.H.E. 45 (dihydroergotamine mesylate) Injection, USP package before attempting to use the product.oIf there are any questions concerning the use of your D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, ask your doctor or pharmacist.. oRead and follow the instructions in the patient instruction booklet which is provided with the D.H.E. 45 (dihydroergotamine mesylate) Injection, USP package before attempting to use the product.. oIf there are any questions concerning the use of your D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, ask your doctor or pharmacist.. 2.Preparing for the InjectionoCarefully examine the ampul (glass vial) of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP for any cracks or breaks, and the liquid for discoloration, cloudiness, or particles. If any of these defects are present, use new ampul, make certain it is intact, and return the defective ampul to your doctor or pharmacy. Once you open an ampul, if it is not used within an hour, it should be thrown away.. oCarefully examine the ampul (glass vial) of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP for any cracks or breaks, and the liquid for discoloration, cloudiness, or particles. If any of these defects are present, use new ampul, make certain it is intact, and return the defective ampul to your doctor or pharmacy. Once you open an ampul, if it is not used within an hour, it should be thrown away.. 3.Locating an Injection SiteoAdminister your subcutaneous injection in the middle of your thigh, well above the knee.. oAdminister your subcutaneous injection in the middle of your thigh, well above the knee.. 4.Drawing the Medication into the Syringea.Wash your hands thoroughly with soap and water.b. Check the dose of your medication.c.Look to see if there is any liquid at the top of the ampul. If there is, gently flick the ampul with your finger to get all the liquid into the bottom portion of the ampul.d.Hold the bottom of the ampul in one hand. Clean the ampul neck with an alcohol wipe using the other hand. To break, place the alcohol wipe around the neck of the ampul and break it open by pressing your thumb against the neck of the ampul.e.Tilt the ampul down at 45 angle. Insert the needle into the solution in the ampul.f.Draw up the medication by pulling back the plunger slowly and steadily until you reach your dose.g.Check the syringe for air bubbles. Hold it with the needle pointing upward. If there are air bubbles, tap your finger against the barrel of the syringe to get the bubbles to the top. Slowly and carefully push the plunger up so that the bubbles are pushed out through the needle and you see drop of medication.h.When there are no air bubbles, check the dose of the medication. If the dose is incorrect, repeat steps e, f, g, and until you draw up the right dose.. a.Wash your hands thoroughly with soap and water.. b. Check the dose of your medication.. c.Look to see if there is any liquid at the top of the ampul. If there is, gently flick the ampul with your finger to get all the liquid into the bottom portion of the ampul.. d.Hold the bottom of the ampul in one hand. Clean the ampul neck with an alcohol wipe using the other hand. To break, place the alcohol wipe around the neck of the ampul and break it open by pressing your thumb against the neck of the ampul.. e.Tilt the ampul down at 45 angle. Insert the needle into the solution in the ampul.. f.Draw up the medication by pulling back the plunger slowly and steadily until you reach your dose.. g.Check the syringe for air bubbles. Hold it with the needle pointing upward. If there are air bubbles, tap your finger against the barrel of the syringe to get the bubbles to the top. Slowly and carefully push the plunger up so that the bubbles are pushed out through the needle and you see drop of medication.. h.When there are no air bubbles, check the dose of the medication. If the dose is incorrect, repeat steps e, f, g, and until you draw up the right dose.. 5.Preparing the Injection SiteoWith new alcohol wipe, clean the selected injection site thoroughly with firm, circular motion from inside to outside. Wait for the injection site to dry before injecting.. oWith new alcohol wipe, clean the selected injection site thoroughly with firm, circular motion from inside to outside. Wait for the injection site to dry before injecting.. 6.Administering the InjectionoHold the syringe/needle in your right hand.oWith your left hand, firmly grasp about 1-inch fold of skin at the injection site.oPush the needle shaft, bevel side up, all the way into the fold of skin at 45 to 90 angle, then release the fold of skin.oWhile holding the syringe with your left hand, use your right hand to draw back slightly on the plunger.oIf you do not see any blood coming back into the syringe, inject the medication by pushing down on the plunger. If you do see blood in the syringe, that means the needle has penetrated vein. If this happens, pull the needle/syringe out of the skin slightly and draw back on the plunger again. If no blood is seen this time, inject the medication.oUse your right hand to pull the needle out of your skin quickly at the same angle you injected it. Immediately press the alcohol wipe on the injection site and rub.. oHold the syringe/needle in your right hand.. oWith your left hand, firmly grasp about 1-inch fold of skin at the injection site.. oPush the needle shaft, bevel side up, all the way into the fold of skin at 45 to 90 angle, then release the fold of skin.. oWhile holding the syringe with your left hand, use your right hand to draw back slightly on the plunger.. oIf you do not see any blood coming back into the syringe, inject the medication by pushing down on the plunger. If you do see blood in the syringe, that means the needle has penetrated vein. If this happens, pull the needle/syringe out of the skin slightly and draw back on the plunger again. If no blood is seen this time, inject the medication.. oUse your right hand to pull the needle out of your skin quickly at the same angle you injected it. Immediately press the alcohol wipe on the injection site and rub.. Rev. 11/19 9614601 6W500 9L J2. Instructions for Use.

STORAGE AND HANDLING SECTION.

Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [see USPControlled Room Temperature]. Use carton to protect contents from light until used.Do not refrigerate or freeze.To assure constant potency, protect the ampuls from light and heat. Administer only if clear and colorless.

WARNINGS SECTION.

WARNINGS. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should only be used where clear diagnosis of migraine headache has been established.. CYP3A4 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 CYP3A4 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 CYP3A4 inhibitors with dihydroergotamine should therefore be avoided (see CONTRAINDICATIONS ). Examples of some of the more potent CYP3A4 inhibitors include: antifungals ketoconazole and itraconazole, the protease inhibitors ritonavir, nelfinavir, and indinavir, and macrolide antibiotics erythromycin, clarithromycin, and troleandomycin. Other less potent CYP3A4 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, 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. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be used by patients with documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS ). It is strongly recommended that D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 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 patients medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be administered (see CONTRAINDICATIONS ).For patients with risk factors predictive of CAD who are determined to have satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of D.H.E. 45 (dihydroergotamine mesylate)Injection, USP take place in the setting of physicians 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP in those patients with risk factors.It is recommended that patients who are intermittent long-term users of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use D.H.E. 45 (dihydroergotamine mesylate) Injection, USP.The systematic approach described above is currently recommended as method to identify patients in whom D.H.E. 45 (dihydroergotamine mesylate) Injection, USP may be used to treat migraine headaches with an acceptable margin of cardiovascular safety.. Cardiac Events and Fatalities. 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. 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 (dihydroergotamine mesylate) Injection, USP; and some have resulted in fatalities. In number of cases, it appears possible that the cerebrovascular events were primary, the D.H.E. 45 (dihydroergotamine mesylate) Injection, USP having been administered in the incorrect belief that the symptoms experienced were 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. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial, peripheral vascular, and colonic ischemia have been reported with D.H.E. 45 (dihydroergotamine mesylate) Injection, USP.D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 history of hypertension treated with dihydroergotamine mesylate injection. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS ).An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1 agonist in study evaluating subjects undergoing cardiac catheterization.

PREGNANCY SECTION.

Pregnancy. Risk SummaryAvailable data from published literature indicate an increased risk of preterm deliverywith D.H.E. 45 use during pregnancy. Avoid use of D.H.E. 45 during pregnancy (see WARNINGS). Data collected over decades have shown no increased risk of major birth defects or miscarriage with the use of dihydroergotamine mesylate during pregnancy. In animal reproduction studies, adverse effects on development were observed following intranasal administration of dihydroergotamine mesylate during pregnancy (decreased fetal body weight and/or skeletal ossification) in rats and rabbits or during pregnancy and lactation in rats (decreased body weight and impaired reproductive function in the offspring) at doses that were not associated with maternal toxicity (see Data). The estimated rate of major birth defects (2.2% to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal Data Intranasal administration of dihydroergotamine mesylate to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weight and/or skeletal ossification at doses of 0.16 mg/day and greater. no-effect level for adverse effects on embryofetal development was not identified in rats. Intranasal administration of dihydroergotamine mesylate to pregnant rabbits throughout organogenesis resulted in decreased skeletal ossification at 3.6 mg/day. The no-effect dose for adverse effects on embryofetal development in rabbits was 1.2 mg/day. Intranasal administration of dihydroergotamine mesylate to female rats throughout pregnancy and lactation resulted in decreased body weight and impaired reproductive function (decreased mating indices) in the offspring at doses of 0.16 mg/day or greater. no-effect dose for adverse effects on pre- and postnatal development in rats was not established. Effects on offspring development occurred at doses below those that produced evidence of 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.

SPL UNCLASSIFIED SECTION.

Absorption. Absolute bioavailability for the subcutaneous and intramuscular route have not been determined; however, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses.Dihydroergotamine mesylate is poorly bioavailable following oral administration.