N5-929 S-032 S-033
`Package Insert
`Page 1
`
`T2001-89
`89014801
`
`D.H.E. 45®
`(dihydroergotamine mesylate)
`Injection, USP
`Rx only
`Prescribing Information
`WARNING
`Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of
`DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and
`macrolide antibiotics. Because CYP 3A4
`inhibition elevates
`the
`serum
`levels of
`DIHYDROERGOTAMINE, the risk for vasospasm leading to cerebral ischemia and/or ischemia of
`the extremities is increased. Hence, concomitant use of these medications is contraindicated.
`(See also CONTRAINDICATIONS and WARNINGS section)
`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´α)-,
`monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is C33H37N5O5⋅CH4O3S.
`The chemical structure is
`
`Dihydroergotamine mesylate
`C33H37N5O5⋅CH4O3S
`Mol. wt. 679.80
`D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is a clear, colorless solution supplied in sterile
`ampuls for I.V., I.M., or subcutaneous administration containing per mL:
`dihydroergotamine mesylate, USP.......................................................................................1 mg
`ethanol, 94% w/w.................................................................................................... 6.2% by vol.
`glycerin..................................................................................................................... 15% by wt.
`water for injection, qs to .................................................................................................... 1 mL
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

`

`N5-929 S-032 S-033
`Package Insert
`Page 2
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`
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Dihydroergotamine binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors. It also binds with high
`affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline α2A, α2B and α, 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´-β-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.
`
`
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
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`N5-929 S-032 S-033
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`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 P450 3A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has
`also been shown to be an inhibitor of cytochrome P450 3A 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 P450 3A metabolism of
`ergotamine (See CONTRAINDICATIONS). No pharmacokinetic interactions involving other cytochrome
`P450 isoenzymes are known.
`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.
`CONTRAINDICATIONS
`There have been a few reports of serious adverse events associated with the coadministration of
`dihydroergotamine and potent CYP 3A4 inhibitors, such as protease inhibitors and macrolide antibiotics,
`resulting in vasospasm that led to cerebral ischemia and/or ischemia of the extremities. The use of potent
`CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin,
`ketoconazole, itraconazole) with dihydroergotamine is, therefore contraindicated (See WARNINGS: CYP
`3A4 Inhibitors).
`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.
`
`
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
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`N5-929 S-032 S-033
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`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 MRDD of 4 mg) or greater. A no effect level for embryo-fetal toxicity
`was not established in rats. Delayed skeletal ossification was also noted in rabbit fetuses following
`intranasal administration of 3.6 mg/day (maternal exposures approximately 7 times human exposures at the
`MRDD) during organogenesis. A no effect level was seen at 1.2 mg/day (maternal exposures
`approximately 2.5 times human exposures at the MRDD). When dihydroergotamine mesylate nasal spray
`was administered intranasally to female rats during pregnancy and lactation, decreased body weights and
`impaired reproductive function (decreased mating indices) were observed in the offspring at doses of 0.16
`mg/day or greater. A no effect level was not established. Effects on development occurred at doses below
`those that produced evidence of significant maternal toxicity in these studies. Dihydroergotamine-induced
`intrauterine growth retardation has been attributed to reduced uteroplacental blood flow resulting from
`prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone.
`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.
`WARNINGS
`D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should only be used where a clear diagnosis of
`migraine headache has been established.
`
`CYP 3A4 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 CYP 3A4 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 CYP 3A4 inhibitors with dihydroergotamine should therefore be
`avoided (see CONTRAINDICATIONS). Examples of some of the more potent CYP 3A4 inhibitors
`include: anti-fungals ketoconazole and itraconazole, the protease inhibitors ritonavir, nelfinavir, and
`indinavir, and macrolide antibiotics erythromycin, clarithromycin, and troleandomycin. Other less
`potent CYP 3A4 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.
`
`
`
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
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`N5-929 S-032 S-033
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`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 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
`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.
`
`
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
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`N5-929 S-032 S-033
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`
`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.)
`Fibrotic Complications: see WARNINGS: Fibrotic Complications
`
`
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
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`N5-929 S-032 S-033
`Package Insert
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`
`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 (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 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.
`
`Nicotine
`Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to
`ergot therapy.
`
`
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 7
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`N5-929 S-032 S-033
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`CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See
`CONTRAINDICATIONS and WARNINGS.
`
`
`
`SSRI’s
`Weakness, hyperreflexia, and incoordination have been reported rarely when 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.
`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® Nasal Spray up
`to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately
`9 to 11 times those in humans receiving the MRDD of 4 mg).
`Pregnancy
`Pregnancy Category X. See CONTRAINDICATIONS.
`Nursing Mothers
`Ergot drugs are known to inhibit prolactin. It is likely that 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,
`
`
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
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`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.
`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. 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. Thus, due to the chronicity of vascular headaches, it is imperative that
`patients be advised not to exceed recommended dosages.
`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.
`
`
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
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`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).*
`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. D.H.E. 45® (dihydroergotamine
`mesylate) Injection, USP, should not be used for chronic daily administration.
`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 25°C (77°F), 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.
`INSTRUCTION FOR PATIENTS ON SUBCUTANEOUS SELF-INJECTION
`Information for the Patient
`D.H.E. 45® (dihydroergotamine mesylate) Injection, USP
`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. 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.
`
`
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 10
`
`

`

`N5-929 S-032 S-033
`Package Insert
`Page 11
`
`
`
`Do not use D.H.E. 45® (dihydroergotamine mesylate) Injection, USP if you:
`(cid:127)
`are pregnant or nursing.
`(cid:127)
`have any disease affecting your heart, arteries, or circulation.
`(cid:127)
`are taking certain anti-HIV medications (protease inhibitors).
`(cid:127)
`are taking a macrolide antibiotic such as toleandomycin, clarithromycin or erythromycin.
`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.
`(cid:127)
`Do you have high blood pressure?
`(cid:127)
`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,
`diabetes, 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?
`Are you using D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Spray or other
`dihydroergotamine mesylate containing drugs on a daily basis?
`Are you taking a protease inhibitor for HIV therapy?
`(cid:127)
`Are you taking a macrolide class of antibiotic?
`(cid:127)
`Serious 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 and protease inhibitors or macrolide antibiotics.
`
`(cid:127)
`(cid:127)
`(cid:127)
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`
`
`
`Opiant Exhibit 2088
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 11
`
`

`

`N5-929 S-032 S-033
`Package Insert
`Page 12
`
`
`
`REMEMBER TO TELL YOUR DOCTOR IF YOU HAVE ANSWERED