Dopamine Hydrochloride in Dextrose

1 INDICATIONS AND USAGE Dopamine Hydrochloride in Dextrose Injection is indicated to improve hemodynamic status in patients in distributive shock, or shock due to reduced cardiac output. Dopamine HCl in Dextrose Injection is a catecholamine indicated to improve hemodynamic status in patients in shock. ( 1 )

2 DOSAGE AND ADMINISTRATION • Correct hypovolemia, acidosis, and hypoxia prior to use. ( 2.1 ) • Administer in a large vein with an infusion pump preferably in an intensive care setting. ( 2.1 ) • Recommended starting dosage in adults and pediatric patients is 2 to 5 mcg/kg/minute as a continuous intravenous infusion. Titrate in 5 to 10 mcg/kg/minute increments based on hemodynamic response and tolerability, up to not more than 50 mcg/kg/minute. ( 2.2 ) • See the Full Prescribing Information for important preparation instructions and drug incompatibilities. ( 2.3 ) 2.1 Administration Instructions Correct Hypovolemia, Acidosis, and Hypoxia Address hypovolemia, acidosis, and hypoxia before initiating Dopamine HCl in Dextrose Injection. If patient does not respond to therapy, suspect occult hypovolemia. Acidosis may reduce the effectiveness of dopamine [see Warnings and Precautions (5.1) ] . Administration Dopamine HCl in Dextrose Injection is a premixed infusion solution that does not require dilution prior to intravenous administration. Administer Dopamine HCl in Dextrose Injection into a large vein [see Warnings and Precautions (5.1) ] with the use of an infusion pump preferably in an intensive care setting. Remove outer wrap (moisture and oxygen barrier) only when ready to administer the product. Discard product if outer wrap is damaged (e.g., tears or holes). Inspect Dopamine HCl in Dextrose Injection for particulate matter and discoloration prior to administration (the solution is clear to slightly yellow). Do not administer if the solution is darker than slightly yellow or the container is damaged. Use higher concentration premixed solutions (e.g., 3,200 mcg/mL or 1,600 mcg/mL strengths) in patients requiring fluid restriction. Discontinuation When discontinuing Dopamine HCl in Dextrose Injection, gradually reduce the infusion rate while expanding blood volume with intravenous fluids [see Warnings and Precautions (5.3) ]. 2.2 Recommended Dosage The recommended starting dosage in adults and pediatric patients is 2 to 5 mcg/kg/minute as a continuous intravenous infusion [see Dosage and Administration (2.3) ] . Titrate the infusion rate in 5 to 10 mcg/kg/minute increments based on hemodynamic response and tolerability, up to but not more than 50 mcg/kg/minute. Infusion rates may be calculated using the following formula: Infusion Rate (mL/hour) = [Dose (mcg/kg/minute) × Weight (kg) × 60 (minutes/hour)] Concentration (mcg/mL) Example calculations for infusion rates are as follows: Example 1: for a 60 kg person at the recommended initial dose of 2 mcg/kg/minute using a 1,600 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/hour) = [2 (mcg/kg/minute) × 60 (kg) × 60 (minutes/hour) ] = 4.5 (mL/hour) 1,600 (mcg/mL) Example 2: for a 70 kg person at a dose of 5 mcg/kg/minute using a 3,200 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/hour) = [5 (mcg/kg/minute) × 70 (kg) × 60 (minutes/hour) ] = 6.56 (mL/hour) 3,200 (mcg/mL) 2.3 Drug Incompatibilities Dopamine HCl in Dextrose Injection is incompatible with the following products; therefore, avoid simultaneous administration (through the same infusion set): • Sodium bicarbonate or other alkalinizing substances, because dopamine is inactivated in alkaline solution. • Blood, because of the risk of pseudoagglutination of red cells • Iron salts Do not add additional medications in the premixed infusion solution.

3 DOSAGE FORMS AND STRENGTHS The following strengths of Dopamine Hydrochloride in 5% Dextrose Injection, USP, are supplied in single-dose flexible plastic containers (the solutions are clear to slightly yellow in appearance): • 1,600 mcg/mL (250 or 500 mL) • 3,200 mcg/mL (250 mL) Each 100 mL contains 5 grams of hydrous dextrose in Water for Injection. Following strengths of Dopamine Hydrochloride in 5% Dextrose Injection, USP, are supplied in single-dose flexible plastic containers (each 100 mL contains 5 grams of hydrous dextrose in Water for Injection): ( 3 ) • 1,600 mcg/mL (250 and 500 mL) • 3,200 mcg/mL (250 mL)

4 CONTRAINDICATIONS Dopamine is contraindicated in patients with pheochromocytoma. Patients with pheochromocytoma. ( 4 )

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 post-approval 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 Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with dopamine. Table 1: Clinically Significant Drug Interactions with Dopamine Halogenated Anesthetics Clinical Impact: Concomitant use may increase cardiac autonomic irritability and can sensitize the myocardium to the action of dopamine which may lead to ventricular arrhythmias and hypertension. Intervention: Monitor cardiac rhythm. Examples: desflurane, enflurane, isoflurane, and sevoflurane. MAO Inhibitors Clinical Impact: Because dopamine is metabolized by monoamine oxidase (MAO), inhibition of this enzyme prolongs and potentiates the effect of dopamine which may result in severe hypertension and cardiac arrhythmia. Intervention: Reduce the recommended starting dosage to no greater than one-tenth (1/10) of the recommended dose in patients who have been treated with MAO inhibitors within two to three weeks prior to the administration of Dopamine HCl in Dextrose Injection. Examples: isocarboxazid, phenelzine, tranylcypromine, rasagiline, selegiline, linezolid. Tricyclic Antidepressants Clinical Impact: Concomitant use may potentiate the cardiovascular effects of dopamine (e.g., hypertension). Intervention: Monitor blood pressure. Examples: amitriptyline, desipramine, doxepin, imipramine, nortriptyline. Vasopressors Clinical Impact: Concomitant use may result in severe hypertension. Intervention: Monitor blood pressure. Examples: norepinephrine, epinephrine, oxytocin. • Halogenated anesthetics : Can sensitize the myocardium to the effects of dopamine and can produce ventricular arrhythmias and hypertension. ( 7 ) • MAO inhibitors : Risk of severe hypertension. Reduce recommended Dopamine HCl in Dextrose Injection dosage. ( 7 ) • Tricyclic antidepressants : Risk of hypertension. Monitor blood pressure. ( 7 ) • Vasopressors : Risk of severe hypertension. Monitor blood pressure. ( 7 )

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 dosages, on a mcg/m 2 basis, of one-third the human starting dosage 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.

12.1 Mechanism of Action Dopamine is a natural catecholamine formed by the decarboxylation of 3,4-dihydroxyphenylalanine (DOPA). It is a precursor to norepinephrine in noradrenergic nerves and is also a neurotransmitter in certain areas of the central nervous system, especially in the nigrostriatal tract, and in a few peripheral sympathetic nerves. Dopamine elicits its pharmacological action by activating dopamine D1 and D2 receptors, beta-1 receptors and alpha-1 receptors. The activation of different receptors leading to its effects are dependent on dopamine dose.

11 DESCRIPTION Dopamine Hydrochloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic, premixed solution of dopamine hydrochloride in 5% dextrose injection for intravenous infusion. Each 100 mL contains 160 mg (1,600 mcg/mL) or 320 mg (3,200 mcg/mL) of dopamine HCl; 5 grams of hydrous dextrose, in Water for Injection, and 50 mg of sodium metabisulfite (a stabilizer); pH = 2.5 to 4.5, and the following osmolar concentrations: 269, or 286 mOsmol/liter, respectively. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. Dopamine HCl is chemically designated 3, 4-dihydroxyphenethylamine hydrochloride (C 8 H 11 NO 2 ∙ HCl), a white crystalline powder freely soluble in water. Dopamine HCl has a molecular weight of 189.64 and it has the following structural formula: Dopamine (also referred to as 3-hydroxytyramine) is a naturally occurring endogenous catecholamine. Dextrose, USP is chemically designated D-glucose monohydrate (C 6 H 12 O 6 ∙ H 2 O), a hexose sugar freely soluble in water. The molecular weight of dextrose (D-glucose) monohydrate is 198.17 and it has the following structural formula: Water for Injection, USP is chemically designated H 2 O. Chemical Structure Chemical Structure

10 OVERDOSAGE Manifestations of overdosage include excessive blood pressure elevation. In the case of accidental overdosage, reduce rate of Dopamine HCl in Dextrose Injection infusion, or temporarily discontinue the Dopamine HCl in Dextrose Injection infusion until the overdosage related adverse reactions resolves. Since dopamine's duration of action is 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).

16 HOW SUPPLIED/STORAGE AND HANDLING Dopamine Hydrochloride in 5% Dextrose Injection, USP, is supplied in 250 and 500 mL single-dose flexible plastic containers (the solutions are clear to slightly yellow in appearance) as follows. Each 100 mL contains 5 grams of hydrous dextrose in Water for Injection. Unit of Sale Total Strength/Total Volume (Concentration) NDC 0409-7809-22 Case of 12 single-dose flexible containers 400 mg/250 mL (1,600 mcg/mL) NDC 0409-0042-12 Case of 12 single-dose flexible containers 400 mg/250 mL (1,600 mcg/mL) NDC 0409-7809-24 Case of 12 single-dose flexible containers 800 mg/500 mL (1,600 mcg/mL) NDC 0409-7810-22 Case of 12 single-dose flexible containers 800 mg/250 mL (3,200 mcg/mL) NDC 0409-1858-12 Case of 12 single-dose flexible containers 800 mg/250 mL (3,200 mcg/mL) Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. Discard unused portion.