Dopamine HCl Injection is indicated to improve hemodynamic status in patients in distributive shock or shock due to reduced cardiac output.

Posology

The recommended starting dosage in adults patients is 2 to 5 mcg/kg/minute as a continuous intravenous infusion [see section 6.2]. Titrate the infusion rate in increments of 5 to 10 mcg/kg/minute based on hemodynamic response and tolerability, but do not exceed 50 mcg/kg/minute.

Infusion rates may be calculated using the following formula:

Infusion Rate (mL/hour) = [Dose (mcg/kg/minute) x Weight (kg) x 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 800 mcg/mL concentration, the infusion rate would be as follows:

Infusion Rate (mL/hour) = [2 (mcg/kg/minute) x 60 (kg) x 60 (minutes/hour)] = 9 (mL/hour)

800 (mcg/mL)

Example 2: for a 70 kg person at a dose of 5 mcg/kg/minute using a 1600 mcg/mL concentration, the infusion rate would be as follows:

Infusion Rate (mL/hour) = [5 (mcg/kg/minute) x 70 (kg) x 60 (minutes/hour)] = 13.13 (mL/hour)

1600 (mcg/mL)

Paediatric population

The safety and efficacy of dopamine in paediatric patients has not been established.

Elderly population

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.

Method of administration

To be administered by intravenous infusion only after dilution with the appropriate diluents. For instructions on dilution of the medicinal product before administration, [see section 6.6].

Tissue Ischemia

Administration of dopamine to patients who are hypotensive from hypovolemia can result in severe peripheral and visceral vasoconstriction, decreased renal perfusion and hypouresis, tissue hypoxia, lactic acidosis, and poor systemic blood flow despite “normal” blood pressure. Address hypovolemia prior to initiating Dopamine HCl Injection [see section 4.2].

Gangrene of the extremities has occurred in patients with occlusive vascular disease or who received prolonged or high dose infusions. Monitor for changes to the skin of the extremities in susceptible patients.

Extravasation of Dopamine HCl Injection may cause necrosis and sloughing of surrounding tissue. To reduce the risk of extravasation, infuse into a large vein [see section 4.2], check the infusion site frequently for free flow, and monitor for signs of extravasation.

Emergency Treatment of Extravasation

To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with:

·       5 to 10 mg of phentolamine mesylate in 10 to 15 mL of 0.9% Sodium Chloride Injection in adults

Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.

Cardiac Arrhythmias

Dopamine may cause arrhythmias. Monitor patients with arrhythmias and treat appropriately.

Hypotension after Abrupt Discontinuation

Sudden cessation of the infusion may result in marked hypotension. Gradually reduce the infusion rate while expanding blood volume with intravenous fluids.

Severe Hypersensitivity Reactions due to Sodium Metabisulfite Excipient

Dopamine HCl Injection contains sodium metabisulfite, 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 than in nonasthmatic people.

See Table 1 for clinically significant drug interactions with dopamine.

Table 1: Clinically Significant Drug Interactions with Dopamine

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 section 5.1]. In animal reproduction studies, adverse developmental outcomes were observed with intravenous dopamine HCl administration in pregnant rats during organogenesis at doses, on a mcg/m² basis, of one‑third the human starting dose of 2 mcg/kg/minute (90 mcg/m²/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 section 4.5].

Data

Animal Data

Animal reproduction studies in rats and rabbits at dopamine HCl dosages up to 6 mg/kg/day intravenously (on a mcg/m² 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/m² 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.

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.

The effect of dopamine hydrochloride on the ability to drive or use machines has not been systematically evaluated.

The following adverse reactions are described elsewhere in the labeling:

·       Tissue Ischemia [see section 4.4]

·       Cardiac Arrhythmias [see section 4.4]

·       Hypotension [see section 4.4]

·       Severe Hypersensitivity Reactions [see section 4.4]

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to National Pharmacovigilance Centre (NPC).

To Report side effects

·     Saudi Arabia

·     Other GCC States

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).

Pharmacotherapeutic group: adrenergic and dopaminergic agents, ATC code: C01CA04

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.

Pharmacodynamic effects

Dopamine’s onset of action occurs within five minutes of intravenous administration and the duration of action is less than about ten minutes. Dopamine effects are dosage‑dependent.

·       At <5 mcg/kg/minute, dopamine HCl activates dopamine D1 and D2 receptors in the renal, mesenteric, and coronary vasculature causing vasodilation.

·       At 5 to 10 mcg/kg/minute, dopamine HCl activates beta‑1 receptors enhancing heart rate and contractility.

·       At >10 mcg/kg/minute, dopamine HCl activates alpha‑1 receptors causing vasoconstriction and increased blood pressure

Distribution

Following intravenous administration, dopamine is widely distributed in the body but does not cross the blood‑brain barrier to a significant extent.

Elimination

The half‑life of dopamine in adults is less than 2 minutes.

Metabolism

About 75% of dopamine is metabolized by monoamine oxidase (MAO) and catechol O‑methyl transferase (COMT) in the liver, kidney, and plasma to the inactive compounds homovanillic acid (HVA) and 3,4‑dihydroxyphenylacetic acid, and about 25% is metabolized to norepinephrine in the adrenergic nerve terminals.

Excretion

About 80% of dopamine is renally excreted as inactive metabolites within 24 hours. Dopamine is stored in vesicles or diffused back into the plasma.

Carcinogenesis

Long term animal studies have not been performed to evaluate the carcinogenic potential of dopamine.

Mutagenesis

Dopamine HCl at doses approaching maximal solubility showed no clear genotoxic potential in the Ames test. Although there was a reproducible dose‑dependent increase in the number of revertant colonies with strains TA100 and TA98, both with and without metabolic activation, the small increase was considered inconclusive evidence of mutagenicity. In the L5178Y TK^+/- mouse lymphoma assay, dopamine HCl at the highest concentrations used of 750 mcg/mL without metabolic activation, and 3000 mcg/mL with activation, was toxic and associated with increases in mutant frequencies when compared to untreated and solvent controls; at the lower concentrations no increases over controls were noted.

No clear evidence of clastogenic potential was reported in the in vivo mouse or male rat bone marrow micronucleus test when the animals were treated intravenously with up to 224 mg/kg and 30 mg/kg of dopamine HCl, respectively.

Sodium metabisulphite, citric acid anhydrous, sodium citrate dihydrate, nitrogen and water for injections

Dopamine HCl 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 diluted infusion solution.

Store at 20 to 25°C (68 to 77°F).  Keep container in the outer carton.

Glass Flip-Top Vial. The product is registered in 2 pack sizes: 5 mL and 10 mL vials

Single-dose vials. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Preparation and Administration Instructions

Correct Hypovolemia, Acidosis, and Hypoxia

Address hypovolemia, acidosis, and hypoxia before initiating Dopamine HCl Injection. If patient does not respond to therapy, suspect occult hypovolemia. Acidosis may reduce the effectiveness of dopamine [see section 4.4].

Preparation

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 HCl Injection to either a 250‑mL or a 500‑mL bottle of one of the sterile intravenous solutions listed below:

·     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:

Dopamine HCl Injection has been found to be stable for 24 hours after dilution in the foregoing intravenous solutions.

Administration

Dopamine HCl Injection is administered (only after dilution) by intravenous infusion.

Administer Dopamine HCl Injection into a large vein [see section 4.4] with the use of an infusion pump preferably in an intensive care setting.

Inspect Dopamine HCl Injection for particulate matter and discoloration prior to administration whenever solution and container permit (the solution is clear, practically colorless). Do not administer if the solution is darker or discolored.

Use higher concentration solutions (e.g., 3200 mcg/mL or 1600 mcg/mL strengths) in patients requiring fluid restriction.

Discontinuation

When discontinuing Dopamine HCl Injection, gradually reduce the infusion rate while expanding blood volume with intravenous fluids [see section 4.4].