Dopamine Hydrochloride

INDICATIONS AND USAGE Dopamine Hydrochloride, USP is indicated for the correction of hemodynamic imbalances present in the shock syndrome due to myocardial infarction, trauma, endotoxic septicemia, open-heart surgery, renal failure, and chronic cardiac decompensation as in congestive failure. Patients most likely to respond adequately to Dopamine Hydrochloride, USP are those in whom physiological parameters, such as urine flow, myocardial function, and blood pressure, have not undergone profound deterioration. Multiclinic trials indicate that the shorter the time interval between onset of signs and symptoms and initiation of therapy with blood volume correction and Dopamine Hydrochloride, USP, the better the prognosis. Where appropriate, blood volume restoration with a suitable plasma expander or whole blood should be accomplished prior to administration of Dopamine Hydrochloride, USP. Poor Perfusion of Vital Organs – Urine flow appears to be one of the better diagnostic signs by which adequacy of vital organ perfusion can be monitored. Nevertheless, the physician should also observe the patient for signs of reversal of confusion or reversal of comatose condition. Loss of pallor, increase in toe temperature, and/or adequacy of nail bed capillary filling may also be used as indices of adequate dosage. Clinical studies have shown that when Dopamine Hydrochloride, USP is administered before urine flow has diminished to levels of approximately 0.3 mL/minute, prognosis is more favorable. Nevertheless, in a number of oliguric or anuric patients, administration of Dopamine Hydrochloride, USP has resulted in an increase in urine flow, which in some cases reached normal levels. Dopamine Hydrochloride, USP may also increase urine flow in patients whose output is within normal limits and thus may be of value in reducing the degree of pre-existing fluid accumulation. It should be noted that at doses above those optimal for the individual patient, urine flow may decrease, necessitating reduction of dosage. Low Cardiac Output – Increased cardiac output is related to dopamine’s direct inotropic effect on the myocardium. Increased cardiac output at low or moderate doses appears to be related to a favorable prognosis. Increase in cardiac output has been associated with either static or decreased systemic vascular resistance (SVR). Static or decreased SVR associated with low or moderate movements in cardiac output is believed to be a reflection of differential effects on specific vascular beds with increased resistance in peripheral beds (e.g., femoral) and concomitant decreases in mesenteric and renal vascular beds. Redistribution of blood flow parallels these changes so that an increase in cardiac output is accompanied by an increase in mesenteric and renal blood flow. In many instances the renal fraction of the total cardiac output has been found to increase. Increase in cardiac output produced by dopamine is not associated with substantial decreases in systemic vascular resistance as may occur with isoproterenol. Hypotension – Hypotension due to inadequate cardiac output can be managed by administration of low to moderate doses of Dopamine Hydrochloride, USP which have little effect on SVR. At high therapeutic doses, dopamine’s alpha-adrenergic activity becomes more prominent and thus may correct hypotension due to diminished SVR. As in the case of other circulatory decompensation states, prognosis is better in patients whose blood pressure and urine flow have not undergone profound deterioration. Therefore, it is suggested that the physician administer Dopamine Hydrochloride, USP as soon as a definite trend toward decreased systolic and diastolic pressure becomes evident.

DOSAGE AND ADMINISTRATION WARNING: This is a potent drug; it must be diluted before administration to the patient. Dopamine hydrochloride injection is administered (only after dilution) by intravenous infusion. Suggested Dilution – For the 40 mg/mL preparation, transfer by aseptic technique the contents containing either 5 mL, 200 mg or 10 mL, 400 mg of dopamine hydrochloride to either a 250 mL or 500 mL bottle of one of the sterile I.V. solutions listed below. For the 80 mg/mL preparation, transfer by aseptic technique the contents containing 10 mL, 800 mg of dopamine hydrochloride to a 250 mL, 500 mL or 1000 mL bottle of one of the following sterile I.V. solutions: 0.9% Sodium Chloride Injection, USP 5% Dextrose Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP 5% Dextrose and Lactated Ringer’s Injection Sodium Lactate Injection, USP 1/6 Molar Lactated Ringer’s Injection, USP The resultant dilutions are summarized in the following chart: Concentration of dopamine hydrochloride 40 mg/mL 80 mg/mL Volume of dopamine Hydrochloride Injection, USP 5 mL 10 mL 10 mL 250 mL Bottle of I.V. Solution 800 mcg/mL 1600 mcg/mL 3200 mcg/mL 500 mL Bottle of I.V. Solution 400 mcg/mL 800 mcg/mL 1600 mcg/mL 1000 mL Bottle of I.V. Solution 200 mcg/mL 400 mcg/mL 800 mcg/mL Dopamine hydrochloride injection has been found to be stable for a minimum of 24 hours after dilution in the foregoing I.V. solutions. However, as with all I.V. admixtures, dilution should be made just prior to administration. Do NOT add dopamine hydrochloride to Sodium Bicarbonate Injection, USP or other alkaline I.V. solutions, since the drug is inactivated in alkaline solution. Rate of Administration – Dopamine hydrochloride injection after dilution, is administered intravenously by infusion via a suitable I.V. catheter or needle. When administering dopamine hydrochloride (or any potent medication) by continuous intravenous infusion, it is advisable to use a precision volume control I.V. set. Each patient must be individually titrated to the desired hemodynamic or renal response to dopamine. In titrating to the desired increase in systolic blood pressure, the optimum dosage rate for renal response may be exceeded, thus necessitating a reduction in rate after the hemodynamic condition is stabilized. Administration at rates greater than 50 mcg/kg/min have safely been used in advanced circulatory decompensation states. If unnecessary fluid expansion is of concern, adjustment of drug concentration may be preferred over increasing the flow rate of a less concentrated dilution. Suggested Regimen: 1. When appropriate, increase blood volume with whole blood or plasma until central venous pressure is 10 to 15 cm H2O or pulmonary wedge pressure is 14 to 18 mm Hg. 2. Begin infusion of diluted solution at doses of 2 – 5 mcg/kg/min of dopamine hydrochloride in patients who are likely to respond to modest increments of heart force and renal perfusion. In more seriously ill patients, begin infusion of diluted solution at doses of 5 mcg/kg/min of dopamine hydrochloride and increase gradually using 5 to 10 mcg/kg/min increments up to a rate of 20 to 50 mcg/kg/min as needed. If doses in excess of 50 mcg/kg/min are required, it is advisable to check urine output frequently. Should urinary flow begin to decrease in the absence of hypotension, reduction of dopamine dosage should be considered. Multiclinic trials have shown that more than 50 percent of patients have been satisfactorily maintained on doses less than 20 mcg/kg/min. In patients who do not respond to these doses with adequate arterial pressures or urine flow, additional increments of dopamine may be given in an effort to produce an appropriate arterial pressure and central perfusion. 3. Treatment of all patients requires constant evaluation of therapy in terms of blood volume, augmentation of cardiac contractility, and distribution of peripheral perfusion. Dosage of …

3 DOSAGE FORMS AND STRENGTHS The following strengths of Dopamine HCL, USP, are supplied in single-dose vials (the solution is clear practically colorless): 200 mg/5 mL (40 mg/mL) 400 mg/10 mL (40 mg/mL) 400 mg/5 mL (80 mg/mL) 800 mg/10 mL (80 mg/mL) The following strengths of Dopamine HCL, USP, are supplied in single-dose vials: ( 3 ) 200 mg/5 mL (40 mg/mL) 400 mg/10 mL (40 mg/mL) 400 mg/5 mL (80 mg/mL) 800 mg/10 mL (80 mg/mL)

CONTRAINDICATIONS Dopamine HCl should not be used in patients with pheochromocytoma. Dopamine HCl should not be administered to patients with uncorrected tachyarrhythmias or ventricular fibrillation.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Tissue Ischemia [see Warnings and Precautions ( 5.1 )] Cardiac Arrhythmias [see Warnings and Precautions ( 5.2 )] Hypotension [see Warnings and Precautions ( 5.3 )] Severe Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] The following adverse reactions have been identified during postapproval use of dopamine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: anginal pain, palpitation Gastrointestinal Disorders: nausea, vomiting Metabolism and Nutrition Disorders: azotemia Nervous System Disorders : headache, anxiety Respiratory Disorders : dyspnea Skin and Subcutaneous Tissue Disorders : piloerection Vascular Disorders : hypertension The most common adverse reaction is localized vasoconstriction due to extravasation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions 1. Because dopamine is metabolized by monoamine oxidase (MAO), inhibition of this enzyme prolongs and potentiates the effect of dopamine. Patients who have been treated with MAO inhibitors within two to three weeks prior to the administration of dopamine HCl should receive initial doses of dopamine HCl no greater than one-tenth (1/10) of the usual dose. 2. Concurrent administration of dopamine HCl and diuretic agents may produce an additive or potentiating effect on urine flow. 3. Tricyclic antidepressants may potentiate the pressor response to adrenergic agents. 4. Cardiac effects of dopamine are antagonized by beta-adrenergic blocking agents , such as propranolol and metoprolol. The peripheral vasoconstriction caused by high doses of dopamine HCl is antagonized by alpha-adrenergic blocking agents . Dopamine-induced renal and mesenteric vasodilation is not antagonized by either alpha- or beta-adrenergic blocking agents. 5. Haloperidol appears to have strong central antidopaminergic properties. Haloperidol and haloperidol-like drugs suppress the dopaminergic renal and mesenteric vasodilation induced at low rates of dopamine infusion. 6. Cyclopropane or halogenated hydrocarbon anesthetics increase cardiac autonomic irritability and may sensitize the myocardium to the action of certain intravenously administered catecholamines, such as dopamine. This interaction appears to be related both to pressor activity and to beta-adrenergic stimulating properties of these catecholamines and may produce ventricular arrhythmias and hypertension. Therefore, EXTREME CAUTION should be exercised when administering dopamine HCl to patients receiving cyclopropane or halogenated hydrocarbon anesthetics. It has been reported that results of studies in animals indicate that dopamine-induced ventricular arrhythmias during anesthesia can be reversed by propranolol. 7. The concomitant use of vasopressors and some oxytocic drugs may result in severe persistent hypertension. See Labor and Delivery below. 8. Administration of phenytoin to patients receiving dopamine HCl has been reported to lead to hypotension and bradycardia. It is suggested that in patients receiving dopamine HCl, alternatives to phenytoin should be used if anticonvulsant therapy is needed.

Labor and Delivery In obstetrics, if vasopressor drugs are used to correct hypotension or are added to a local anesthetic solution, some oxytocic drugs may cause severe persistent hypertension and may even cause rupture of a cerebral blood vessel to occur during the postpartum period.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no human data with dopamine use in pregnant women. There are risks to the mother and fetus from hypotension associated with shock, which can be fatal if left untreated ( see Clinical Considerations ). In animal reproduction studies, adverse developmental outcomes were observed with intravenous dopamine HCl administration in pregnant rats during organogenesis at doses, on a mcg/m 2 basis, of one-third the human starting dose of 2 mcg/kg/minute (90 mcg/m 2 /minute). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal risk Hypotension associated with distributive shock, or shock due to reduced cardiac output are medical emergencies in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with distributive shock, or shock due to reduced cardiac output may increase the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of dopamine on the fetus. Labor or Delivery Vasopressor drugs, including dopamine, may cause severe maternal hypertension when used concomitantly with some oxytocic drugs [see Drug Interactions ( 7 )] . Data Animal Data Animal reproduction studies in rats and rabbits at dopamine HCl dosages up to 6 mg/kg/day intravenously (on a mcg/m 2 basis, one third and two thirds, respectively, the human starting dosage of 2 mcg/kg/minute) during organogenesis produced no detectable teratogenic or embryotoxic effects, although maternal toxicity consisting of mortalities, decreased body weight gain, and pharmacotoxic signs were observed in rats. In a published study, administration of 10 mg/kg/day dopamine HCl (on a mcg/m 2 basis, two-thirds the human starting dosage of 2 mcg/kg/minute) to pregnant rats throughout gestation or for 5 days starting on gestation day 10 or 15 resulted in decreased body weight gain, increased mortality, and slight increase in cataract formation among the offspring. 8.2 Lactation Risk Summary There are no data regarding the presence of dopamine in human milk, the effects of dopamine on the breastfed infant, or the effects of the drug on milk production. 8.4 Pediatric Use Dopamine HCl infusions have been used in pediatric patients from birth through adolescence. Most reports in pediatric patients describe dosing that is similar (on a mcg/kg/minute basis) to that used in adults [see Dosage and Administration ( 2.2 )] . Except for vasoconstrictive effects caused by inadvertent infusion of dopamine into the umbilical artery, adverse reactions unique to pediatric patients have not been identified, nor have adverse reactions identified in adults been found to be more common in pediatric patients. 8.5 Geriatric Use Clinical studies of dopamine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

DESCRIPTION Dopamine Hydrochloride, USP a sympathomimetic amine vasopressor, is the naturally occurring immediate precursor of norepinephrine. Dopamine Hydrochloride, USP is a white to off-white crystalline powder, which may have a slight odor of hydrochloric acid. It is freely soluble in water and soluble in alcohol. Dopamine Hydrochloride, USP is sensitive to alkalies, iron salts, and oxidizing agents. Chemically it is designated as 4-(2-aminoethyl) pyrocatechol hydrochloride, and its molecular formula is C 8 H 11 NO 2 • HCl. The structural formula is: and the molecular weight is 189.64. Dopamine Hydrochloride Injection, USP is a clear, practically colorless, sterile, pyrogen-free, aqueous solution of Dopamine Hydrochloride, USP for intravenous infusion after dilution. Each milliliter of the 40 mg/mL preparation contains 40 mg of Dopamine Hydrochloride, USP (equivalent to 32.31 mg of dopamine base). Each milliliter of the 80 mg/mL preparation contains 80 mg of Dopamine Hydrochloride, USP (equivalent to 64.62 mg of dopamine base). Each milliliter of both preparations contains the following: Sodium metabisulfite 9 mg added as an antioxidant; citric acid, anhydrous 10 mg; and sodium citrate, dihydrate 5 mg added as a buffer. May contain additional citric acid and/or sodium citrate for pH adjustment. pH is 3.3 (2.5 to 5.0). Dopamine Hydrochloride Injection, USP must be diluted in an appropriate sterile parenteral solution before intravenous administration. (See DOSAGE AND ADMINISTRATION ) structure

10 OVERDOSAGE Manifestations of overdosage include excessive blood pressure elevation. In the case of accidental overdosage, reduce rate of Dopamine HCl Injection administration or temporarily discontinue the dopamine HCl until the overdosage related adverse reactions resolves. Since dopamine’s duration of action is quite short, no additional remedial measures are usually necessary. If these measures fail to resolve the overdosage related adverse reactions, consider using an alpha-adrenergic blocking agent (e.g., phentolamine).

HOW SUPPLIED DOPAMINE HYDROCHLORIDE INJECTION, USP 200mg/5mL s supplied in the following dosage forms. NDC 51662-1489-1 DOPAMINE HYDROCHLORIDE INJECTION, USP 200mg/5mL (40mg/mL) 5mL VIAL NDC 51662-1489-2 DOPAMINE HYDROCHLORIDE INJECTION, USP 200mg/5mL (40mg/mL) 5mL VIAL, 1 VIAL/POUCH NDC 51662-1489-3 DOPAMINE HYDROCHLORIDE INJECTION, USP 200mg/5mL (40mg/mL) 5mL VIAL, 1 VIAL/POUCH, 25 POUCHES/CASE HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Dopamine Hydrochloride Injection, USP is a clear, colorless to slightly yellow aqueous solution supplied as follows: Avoid contact with alkalies (including sodium bicarbonate), oxidizing agents or iron salts. Do not use the injection if it is darker than slightly yellow or discolored in any other way. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]