`International Medication Systems, Limited
`Disclaimer: This drug has not been found by FDA to be safe and effective, and this labeling has not been
`approved by FDA. For further information about unapproved drugs, click here.
`----------
`EPINEPHRINE INJECTION,
`USP, 1:1000
`
`DESCRIPTION:
`Epinephrine Injection, USP, is a sterile, nonpyrogenic solution intended for subcutaneous or
`intramuscular injection. When diluted, it may also be administered intracardially or intravenously. Each
`mL contains: 1 mg Epinephrine as the hydrochloride, in Water for Injection, USP, q.s. Sodium Chloride
`added for isotonicity, 0.5% Chlorobutanol (chloroform derivative) as a preservative and not more than
`0.15% Sodium Metabisulfite as an antioxidant. The pH may be adjusted with Sodium Hydroxide and/ or
`Hydrochloric Acid. Epinephrine is the active principle of the adrenal medulla, chemically described as
`(-)-3,4-Dihydroxy-α-[(methylamino)methyl]benzyl alcohol, and has the following structural formula:
`
`CLINICAL PHARMACOLOGY:
`Epinephrine is a sympathomimetic drug. It activates an adrenergic receptive mechanism on effector
`cells and imitates all actions of the sympathetic nervous system except those on the arteries of the face
`and sweat glands. Epinephrine acts on both alpha and beta receptors and is the most potent alpha receptor
`activator.
`Epinephrine relaxes the smooth muscle of the bronchi and iris and is a physiologic antagonist of
`histamine. The drug also produces an increase in blood sugar and glycogenolysis in the liver.
`
`Pharmacokinetics:
`Intravenous injection produces an immediate and intensified response. Following I.V. injection,
`epinephrine disappears rapidly from the blood stream. Subcutaneously or I.M. administered epinephrine
`has a rapid onset and short duration of action. Subcutaneous administration during asthmatic attacks may
`produce bronchodilation within 5 to 10 minutes, and maximal effects may occur within 20 minutes.
`The drug becomes fixed in the tissues and is rapidly inactivated chiefly by enzymic transformation to
`metanephrine or normetanephrine, either of which is subsequently conjugated and excreted in the urine
`in the form of sulfates and glucuronides. Either sequence results in the formation of 3-methoxy-4-
`hydroxy-mandelic acid(vanillylmandelic acid, VMA) which is also detectable in the urine.
`
`INDICATIONS AND USAGE:
`In general, the most common uses of epinephrine are to relieve respiratory distress due to
`bronchospasm, to provide rapid relief of hypersensitivity reactions to drugs and other allergens, and to
`prolong the action of infiltration anesthetics. Its cardiac effects may be of use in restoring cardiac
`rhythm in cardiac arrest due to various causes, but is not used in cardiac failure or in hemorrhagic,
`
`ADAMIS EXHIBIT 1018
`Page 1 of 8
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`
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`rhythm in cardiac arrest due to various causes, but is not used in cardiac failure or in hemorrhagic,
`traumatic, or cardiogenic shock.
`Epinephrine is used as a hemostatic agent. It is also used in treating mucosal congestion of hay fever,
`rhinitis, and acute sinusitis; to relieve bronchial asthmatic paroxysms; in syncope due to complete heart
`block or carotid sinus hypersensitivity; for symptomatic relief of serum sickness, urticaria,
`angioneurotic edema; for resuscitation in cardiac arrest following anesthetic accidents; in simple (open
`angle) glaucoma; for relaxation of uterine musculature and to inhibit uterine contractions. Epinephrine
`injection can be utilized to prolong the action of local anesthetics (see CONTRAINDICATIONS).
`
`CONTRAINDICATIONS:
`Epinephrine is contraindicated in narrow angle (congestive) glaucoma, shock, during general anesthesia
`with halogenated hydrocarbons or cyclopropane and in individuals with organic brain damage.
`Epinephrine is also contraindicated with local anesthesia of certain areas, e.g., fingers, toes, because of
`the danger of vasoconstriction producing sloughing of tissue; in labor because it may delay the second
`stage; in cardiac dilatation and coronary insufficiency.
`Epinephrine should not be used in those cases where vasopressor drugs may be contraindicated, e.g., in
`thyrotoxicosis, diabetes, in obstetrics when maternal blood pressure is in excess of 130/80, and in
`hypertension and other cardiovascular disorders.
`
`WARNINGS:
`Administer with caution to elderly people; to those with cardiovascular disease, hypertension, diabetes,
`or hyperthyroidism; in psychoneurotic individuals; and in pregnancy.
`Patients with long-standing bronchial asthma and emphysema who have developed degenerative heart
`disease should be administered the drug with extreme caution.
`Overdosage or inadvertent intravenous injection of epinephrine may cause cerebrovascular hemorrhage
`resulting from the sharp rise in blood pressure. (See OVERDOSAGE)
`Fatalities may also result from pulmonary edema because of the peripheral constriction and cardiac
`stimulation produced. Rapidly acting vasodilators, such as nitrites, or alpha blocking agents may
`counteract the marked pressor effects of epinephrine.
`Epinephrine contains sodium bisulfite, a sulfite that may cause allergic-type reactions including
`anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible
`people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably
`low. Sulfite sensitivity is seen more frequently in asthmatic rather than in non-asthmatic people.
`Epinephrine is the preferred treatment of serious allergic or other emergency situations even though
`this product contains sodium metabisulfite, a sulfite that may in other products cause allergic-type
`reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in
`certain susceptible persons. The alternative to using epinephrine in a life-threatening situation may not
`be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for
`treatment of serious allergic or other emergency situations.
`Cardiovascular effects: Inadvertently induced high arterial blood pressure may result in angina
`pectoris (especially when coronary insufficiency is present), or aortic rupture.
`Epinephrine may induce potentially serious cardiac arrhythmias in patients not suffering from heart
`disease and patients with organic heart disease or who are receiving drugs that sensitize the
`myocardium. With Epinephrine 1:1,000, a paradoxical but transient lowering of blood pressure,
`bradycardia and apnea may occur immediately after injection.
`Cerebrovascular hemorrhage: Overdosage or inadvertent I.V. injection of epinephrine may cause
`cerebrovascular hemorrhage resulting from the sharp rise in blood pressure.
`
`ADAMIS EXHIBIT 1018
`Page 2 of 8
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`
`Pulmonary edema: Fatalities may also result from pulmonary edema because of the peripheral
`constriction and cardiac stimulation produced.
`
`PRECAUTIONS:
`General: Epinephrine injection should be protected from exposure to light. Do not remove vial from
`carton until ready to use. The solution should not be used if it is pinkish or darker than slightly yellow
`or if it contains a precipitate.
`Epinephrine is readily destroyed by alkalies and oxidizing agents. In the latter category are oxygen,
`chlorine, bromine, iodine, permanganates, chromates, nitrites, and salts of easily reducible metals,
`especially iron.
`
`Drug Interactions:
`Use of epinephrine with excessive doses of digitalis, mercurial diuretics, or other drugs that sensitize
`the heart to arrhythmias is not recommended. Anginal pain may be induced when coronary insufficiency
`is present.
`The effects of epinephrine may be potentiated by tricyclic antidepressants; certain antihistamines, e.g.,
`diphenhydramine, tripelennamine, d-chlorpheniramine; and sodium I-thyroxine.
`In obstetrics, if vasopressor drugs are used either to correct hypotension or added to the local
`anesthetic solution, some oxytocic drugs may cause severe persistent hypertension; even rupture of a
`cerebral blood vessel may occur during the postpartum period.
`All vasopressors should be used cautiously in patients taking monoamine oxidase (MAO) inhibitors.
`Cyclopropane or halogenated hydrocarbon anesthetics such as halothane which sensitize the
`myocardium administration of a beta-adrenergic blocking drug.
`Diuretic agents may decrease vascular response to pressor drugs such as epinephrine.
`Epinephrine may antagonize the neuron blockade produced by guanethidine resulting in decreased
`antihypertensive effect and requiring increased dosage of the latter.
`Use of epinephrine with excessive doses of digitalis, mercurial diuretics or other drugs that sensitize
`the heart to arrhythmias is not recommended.
`Rapidly acting vasodilators such as nitrites or alpha-blocking agents may counteract the marked
`pressor effects of epinephrine.
`Propranolol administered concomitantly with epinephrine may block the beta-adrenergic effects of
`epinephrine, causing hypertension.
`
`PREGNANCY:
`Teratogenic effects: Pregnancy Category C. Epinephrine has been shown to be teratogenic in rats when
`given in doses about 25 times the human dose. There are not adequate and well-controlled studies in
`pregnant women. Epinephrine should be used during pregnancy only if the potential benefit justifies the
`potential risk to the fetus.
`Usage in Labor and Delivery: Parenteral administration of epinephrine, if used to support blood
`pressure during low or other spinal anesthesia for delivery, can cause acceleration of fetal heart rate
`and should not be used in obstetrics when maternal blood pressure exceeds 130/80.
`Usage in Children: Epinephrine should be administered with caution to infants and children. Syncope
`has occurred following the administration of epinephrine to asthmatic children.
`
`ADVERSE REACTIONS:
`
`ADAMIS EXHIBIT 1018
`Page 3 of 8
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`
`
`Transient and minor side effects of anxiety, headache, fear, and palpitations often occur with therapeutic
`doses, especially in hyperthyroid individuals. Repeated local injections can result in necrosis at sites of
`injection from vascular constriction. “Epinephrine-fastness” can occur with prolonged use.
`Local: Repeated local injections can result in necrosis at sites of injection from vascular constriction.
`Systemic: Cerebral hemorrhage; hemiplegia; subarachnoid hemorrhage; anginal pain in patients with
`angina pectoris; anxiety; restlessness; throbbing headache; tremor; weakness; dizziness; pallor;
`respiratory difficulty; palpitation; apprehensiveness; sweating; nausea; vomiting.
`
`OVERDOSAGE:
`Symptoms: Erroneous administration of large doses of epinephrine may lead to precordial distress,
`vomiting, headache, dyspnea, as well as unusually elevated blood pressure.
`Treatment: Most toxic effects can be counteracted by injection of an alpha-adrenergic blocker and a
`beta-adrenergic blocker. In the event of a sharp rise in blood pressure, rapid acting vasodilators such as
`the nitrites, or alpha-adrenergic blocking agents can counteract the marked pressor effects. If prolonged
`hypotension follows, it may be necessary to administer another pressor drug, such as norepinephrine.
`If an epinephrine overdose induces pulmonary edema that interferes with respiration, treatment consists
`of a rapidly acting alpha-adrenergic blocking drug such as phentolamine and/or intermittent positive
`pressure respiration. Treatment of cardiac consists of a beta-adrenergic blocking drug such as
`propranolol.
`Epinephrine overdosage can also cause transient bradycardia followed by tachycardia; these may be
`accompanied by potentially fatal cardiac arrhythmias. Ventricular premature contractions may appear
`within one minute after injection and may be followed by multifocal ventricular tachycardia
`(prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia, and
`occasionally, by atrioventricular block.
`Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis and kidney
`failure. Take suitable corrective measures.
`
`DOSAGE AND ADMINISTRATION:
`Subcutaneously or intramuscularly - 0.2 to 1 mL (mg). Start with a small dose and increase if required.
`Note: The subcutaneous is the preferred route of administration. If given intramuscularly, injection into
`the buttocks should be avoided.
`For bronchial asthma and certain allergic manifestations, e.g., angioedema, urticaria, serum sickness,
`anaphylactic shock, use epinephrine subcutaneously. For bronchial asthma in pediatric patients,
`administer 0.01 mg/kg or 0.3 mg/m2 to a maximum of 0.5 mg subcutaneously, repeated every four hours
`if required.
`For cardiac resuscitation - A dose of 0.5 mL (0.5 mg) diluted to 10 mL with sodium chloride injection,
`can be administered intravenously or intracardially to restore myocardial contractility. External cardiac
`massage should follow intracardial administration to permit the drug to enter coronary circulation. The
`drug should be used secondarily to unsuccessful attempts with physical or electromechanical methods.
`Parenteral drug products should be inspected visually for particulate matter and discoloration whenever
`solution and container permit.
`
`HOW SUPPLIED:
`Epinephrine Injection, USP 1:1000 (1 mg/mL) Packaged individually.
`NDC 76329-9061-0 30 mL Multiple Dose Vial Stock No. 9061
`
`ADAMIS EXHIBIT 1018
`Page 4 of 8
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`
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`Store at Controlled room temperature 15° to 25°C (59° to 77°F). Protect from light and freezing.
`International Medication Systems, Limited
`So. El Monte, CA 91733, U.S.A. Rx Only
`An Amphastar Pharmaceuticals Company REV. 8-11
`
`Epinephrine Injection, USP, 1:1000 - Vial Label
`EPINEPHRINE INJECTION, USP
`1:1000
`(1 mg/mL)
`30 mL
`MULTIDOSE VIAL
`FOR SC AND IM USE
`FOR IV AND IC USE
`AFTER DILUTION
`NDC 76329-9061-0
`Each mL contains:
`1 mg Epinephrine as the hydrochloride, Water for Injection (q.s.). Sodium Chloride added for
`isotonicity. 0.5% Chlorobutanol as a preservative and not more than 0.15% Sodium Metabisulfite as an
`antioxidant. pH may be adjusted with Sodium Hydroxide and/or Hydrochloric Acid.
`Store between 15° & 25°C (59° and 77°F)
`Protect from light and freezing.
`Usual dosage: See Insert.
`7390610C
`Rev. 8-11
`Rx Only
`IMS LIMITED
`SO EL MONTE, CA 91733, USA
`
`ADAMIS EXHIBIT 1018
`Page 5 of 8
`
`
`
`Epinephrine Injection, USP, 1:1000 - Carton
`NDC 76329-9061-0
`MULTIPLE DOSE VIAL
`EPINEPHRINE INJECTION, USP
`1:1000
`(1 mg/mL)
`For SC and IM Use
`For IV and IC Use After Dilution
`30 mL
`IMS LIMITED
`SO EL MONTE CA 91733 USA
`An Amphastar Pharmaceuticals Company
`
`ADAMIS EXHIBIT 1018
`Page 6 of 8
`
`
`
`EPINEPHRINE
`epinephrine injection
`
`Product Information
`Product T ype
`
`Route of Administration
`
`HUMAN PRESCRIPTION DRUG
`
`Ite m Code (Source )
`
`NDC:76 329 -9 0 6 1
`
`PARENTERAL
`
`DEA Sche dule
`
`
`
`Active Ingredient/Active Moiety
`Ingredient Name
`
`Basis of Strength
`
`Strength
`
`ADAMIS EXHIBIT 1018
`Page 7 of 8
`
`
`
`Epinephrine (UNII: YKH8 34O4BH) (Epinephrine - UNII:YKH8 34O4BH)
`
`Epinephrine
`
`1 mg in 1 mL
`
`Packaging
`
`#
`
`Item Code
`
`1 NDC:76 329 -9 0 6 1-
`0
`
`1 in 1 CARTON
`
`Package Description
`
`Marketing Start
`Date
`
`Marketing End
`Date
`
`1
`
`30 mL in 1 VIAL, MULTI-DOSE; Type 0 : No t a Co mbinatio n
`Pro duct
`
`Marketing Information
`Marke ting Cate gory
`Application Numbe r or Monograph Citation Marke ting Start Date Marke ting End Date
`UNAPPROVED DRUG OTHER
`0 7/0 1/20 0 0
`
`Labeler - International Medication Systems, Limited (055750020)
`
`Establishment
`Name
`Internatio nal Medicatio n Systems,
`Limited
`
`Revised: 5/2015
`
`
`
`Addre ss
`
`Busine ss Ope rations
`ID/FEI
`0 55750 0 20 analysis(76 329 -9 0 6 1) , manufacture(76 329 -9 0 6 1) , label(76 329 -
`9 0 6 1)
`
`International Medication Systems, Limited
`
`ADAMIS EXHIBIT 1018
`Page 8 of 8
`
`