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Dihydroergotamine Mesylate

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Overview

What is D.H.E. 45?

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´α)-, monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is CHNO•CHOS.

The chemical structure is:

D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is a clear, colorless solution supplied in sterile ampuls for intravenous, intramuscular, or subcutaneous administration. Each mL contains 1 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).



What does D.H.E. 45 look like?



What are the available doses of D.H.E. 45?

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What should I talk to my health care provider before I take D.H.E. 45?

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How should I use D.H.E. 45?

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.

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. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be used for chronic daily administration.


What interacts with D.H.E. 45?

There have been a 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 ( ).


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 Prinzmetal's variant angina. (.)


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-HT 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 embryofetal development studies of dihydroergotamine mesylate nasal spray, intranasal administration to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weights and/or skeletal ossification at doses of 0.16 mg/day (associated with maternal plasma dihydroergotamine exposures [AUC] approximately 0.4-1.2 times the exposures in humans receiving the MRDD of 4 mg) or greater. A no effect level for 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 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. ()


Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.



What are the warnings of D.H.E. 45?

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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 CYPA4 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 (). 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 ().

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. (.) 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. (.)

For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of 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. (.)

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT agonist in a study evaluating subjects undergoing cardiac catheterization.


What are the precautions of D.H.E. 45?

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 .)

Information for Patients

The text of a patient information sheet is printed at the end of this insert. To assure safe and effective use of 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).

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 ().

Drug Interactions

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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.

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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. (.)

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Although the results of a clinical study did not indicate a 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.

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Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy.

CYP3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors) (

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Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT 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.

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The effect of oral contraceptives on the pharmacokinetics of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP has not been studied.

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Carcinogenesis, Mutagenesis, Impairment of Fertility

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Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing.

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Dihydroergotamine mesylate was clastogenic in two 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 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 mouse and hamster micronucleus tests.

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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 Nasal Spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately 9 to 11 times those in humans receiving the MRDD of 4 mg).

Pregnancy

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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. (.)

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.


What are the side effects of D.H.E. 45?

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 , , and .) Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate ( ).

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. A causal relationship has not been established.

D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is not recommended for prolonged daily use. (.)

To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC, at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


What should I look out for while using D.H.E. 45?

There have been a 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 ( ).

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 Prinzmetal's variant angina. (.)

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-HT 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 embryofetal development studies of dihydroergotamine mesylate nasal spray, intranasal administration to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weights and/or skeletal ossification at doses of 0.16 mg/day (associated with maternal plasma dihydroergotamine exposures [AUC] approximately 0.4-1.2 times the exposures in humans receiving the MRDD of 4 mg) or greater. A no effect level for 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 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. ()

Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.

D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should only be used where a clear diagnosis of migraine headache has been established.


What might happen if I take too much D.H.E. 45?

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 (PDR).


How should I store and handle D.H.E. 45?

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). 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.Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). 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.Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). 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.Hydrocodone bitartrate and ibuprofen tablets, , are supplied as white, round, film-coated, biconvex tablets, debossed with “IP” over “145” on one side and plain on the other side. They are available as follows: Unit dose packages of 100 (10 x 10) NDC 68084-841-01 StorageFOR YOUR PROTECTION:DEA Order Form Required.Hydrocodone bitartrate and ibuprofen tablets, , are supplied as white, round, film-coated, biconvex tablets, debossed with “IP” over “145” on one side and plain on the other side. They are available as follows: Unit dose packages of 100 (10 x 10) NDC 68084-841-01 StorageFOR YOUR PROTECTION:DEA Order Form Required.Hydrocodone bitartrate and ibuprofen tablets, , are supplied as white, round, film-coated, biconvex tablets, debossed with “IP” over “145” on one side and plain on the other side. They are available as follows: Unit dose packages of 100 (10 x 10) NDC 68084-841-01 StorageFOR YOUR PROTECTION:DEA Order Form Required.Hydrocodone bitartrate and ibuprofen tablets, , are supplied as white, round, film-coated, biconvex tablets, debossed with “IP” over “145” on one side and plain on the other side. They are available as follows: Unit dose packages of 100 (10 x 10) NDC 68084-841-01 StorageFOR YOUR PROTECTION:DEA Order Form Required.Hydrocodone bitartrate and ibuprofen tablets, , are supplied as white, round, film-coated, biconvex tablets, debossed with “IP” over “145” on one side and plain on the other side. They are available as follows: Unit dose packages of 100 (10 x 10) NDC 68084-841-01 StorageFOR YOUR PROTECTION:DEA Order Form Required.


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Clinical Information

Chemical Structure

No Image found
Clinical Pharmacology

Dihydroergotamine binds with high affinity to 5-HTα and 5-HTβ receptors. It also binds with high affinity to serotonin 5-HT, 5-HT, and 5-HTreceptors, noradrenaline α, α and α receptors, and dopamine D and D receptors.

The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT receptors. Two current theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT 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-HT receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

In addition, dihydroergotamine possesses oxytocic properties. ()

Non-Clinical Toxicology
There have been a 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 ( ).

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 Prinzmetal's variant angina. (.)

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-HT 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 embryofetal development studies of dihydroergotamine mesylate nasal spray, intranasal administration to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weights and/or skeletal ossification at doses of 0.16 mg/day (associated with maternal plasma dihydroergotamine exposures [AUC] approximately 0.4-1.2 times the exposures in humans receiving the MRDD of 4 mg) or greater. A no effect level for 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 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. ()

Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.

D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should only be used where a clear diagnosis of migraine headache has been established.

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 .)

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 , , and .) Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate ( ).

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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Tips

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Interactions

Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).