Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action Dihydroergotamine binds with high affinity to 5-HT1Da and 5-HT1Db receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline a2A, a2B and a 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 arterio-venous 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'-b-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 a metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20%-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%-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 a terminal half-life of about 9 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 (increased blood levels) have been reported in patients treated orally with dihydroergotamine and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P450 3A metabolism of dihydroergotamine by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

INDICATIONS 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. DOSAGE AND ADMINISTRATION D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should be administered in a dose of 1 mL intravenously, intramuscularly or subcutaneously. The dose can be repeated, as needed, at 1 hour intervals to a total dose of 3 mL for intramuscular or subcutaneous delivery or 2 mL for intravenous delivery in a 24 hour period. The total weekly dosage should not exceed 6 mL. HOW SUPPLIED D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Available as a clear, colorless, sterile solution in single 1 mL sterile ampuls containing 1 mg of dihydroergotamine mesylate per mL, in packages of 10 (NDC 0078-0041-01). Store below 77° F(25° C), in light-resistant containers. Do not refrigerate or freeze. To assure constant potency, protect the ampuls from light and heat. Administer only if clear and colorless.

PATIENT INFORMATION 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 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, below.) INSTRUCTION FOR PATIENTS ON SUBCUTANEOUS SELF-INJECTION Before 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 Medication D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is intended to treat an active migraine headache. Do not try to use it to prevent a headache if you have no symptoms. Do not use it to treat common tension headache or a headache that is not at all typical of your usual migraine headache. Do not use D.H.E. 45® (dihydroergotamine mesylate) Injection, USP If you: are pregnant or nursing. have any disease affecting your heart, arteries, or circulation. Important questions to consider before using D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Please 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. Do you have high blood pressure? Do you have chest pain, shortness of breath, heart disease, or have you had any surgery on your heart arteries? Do you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabates, smoking, strong family history of heart disease, or you are postmenopausal or a male over 40)? Do you have any problems with blood circulation in your arms or legs, fingers, or toes? Are 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 breast feeding? Have you ever had to stop taking this or any other medication because of an allergy or bad reaction? Are 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 a doctor's prescription? Do you smoke? Have you had or do you have, any disease of the liver or kidney? Is this headache different from your usual migraine attacks? 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, USP Side Effects To Watch Out For Although the following reactions rarely occur, they can be serious and should be reported to your physician immediately: Numbness or tingling in your fingers and toes. Pain, tightness, or discomfort in your chest. Muscle pain or cramps in your arms and legs. Weakness in your legs. Temporary speeding or slowing of your heart rate. Swelling or itching. Dosage Your 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 6 hours have elapsed since your last injection. No more than 6 ml of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should be injected during a one-week period. Learn what to do in case of an Overdose If 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, USP 1. Use available training materials. Read 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. If 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 Injection . Carefully 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 a 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 Site Administer your subcutaneous injection in the middle of your thigh, well above the knee. 4. Drawing the Medication into the Syringe Wash your hands thoroughly with soap and water. Check the dose of your medication 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. Hold the bottom of the ampul in one hand. Clean the ampul neck with an alcohol wipe using your other hand. Then place the alcohol wipe around the neck of the ampul and break it open by pressing your thumb against the neck of the ampul. Tilt the ampul down at a 45° angle. Insert the needle into the solution in the ampul. Draw up the medication by pulling back the plunger slowly and steadily until you reach your dose. 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 a drop of medication. When there are no air bubbles check the dose of the medication. If the dose is incorrect, repeat steps 6 through 8 until you draw up the right dose. 5. Preparing the Injection Site. With a new alcohol wipe, clean the selected injection site thoroughly with a firm, circular motion from inside to outside. Wait for the injection site to dry before injecting. 6. Administering the Injection Hold the syringe/needle in your right hand. With your left hand, firmly grasp about a 1-inch fold of skin at the injection site. Push the needle shaft, bevel side up, all the way into the fold of skin at a 45° to 90° angle, then release the fold of skin. While holding the syringe with your left hand, use your right hand to draw back slightly on the plunger. If 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 a 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. Use 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 an 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, USP What if I need help in using my D.H.E. 45® (dihydroergotamine mesylate) Injection, USP? If 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 I use and how often? Your 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 6 hours have elapsed since your last injection. No more than 6 mL of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should be injected during a one-week period. Do not use more than this amount unless instructed to do so by your doctor. If you have any other unanswered question about D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, consult your doctor or pharmacist.

OVERDOSE 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 a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physician's Desk Reference® (PDR). CONTRAINDICATIONS D.H.E. 45® (dihydroergotamine mesylate) Injection, USP 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 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 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 embryo-fetal 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 MADE 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. 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.

SIDE EFFECTS 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) Post-Introduction Reports The following events derive 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. A 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) 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. That, due to the chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages. 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 a clinical study did not indicate a safe 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 a greater ischemic response to ergot therapy. Macrolide Antibiotics (e. g. erythromycin and troleandomycin): Agents of the ergot alkaloid class, of which D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is a member, have been shown to interact with antibiotics of the macrolide class, resulting in increased plasma levels of unchanged alkaloids and peripheral vasoconstriction. Vasospastic reactions have been reported with therapeutic doses of ergotamine-containing drugs when co-administered with these antibiotics. SSRI's: Weakness hyperreflexia, and incoordination have been reported rarely when 5-HT1 agonists have been co-administered 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 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.

WARNINGS D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should only be used where a clear diagnosis of migraine headache has been established. 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 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 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 a satisfactory cardiavascular 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 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 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 a 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 a 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 a consequence of migraine when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. stroke, hemorrhage, transient ischemic attack). Other Vasospasm Related Events 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 a 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 a study evaluating subjects undergoing cardiac catheterization. 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 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) 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 mosylate) Injection, USP. There was no evidence of impairment of fertility in rats given intranasal doses of Migranal® 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 MADE of 4 mg). Pregnancy Pregnancy Category X: See CONTRAINDICATIONS. 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.