Excessive elevation of blood pressure and vasoconstriction can occur due to the alpha adrenergic actions of Dofamine, especially in patients with a history of occlusive vascular disease. If desired, this condition can be rapidly reversed by dose reduction or discontinuing the infusion, since Dofamine has a half-life of less than 2 minutes in the body.
Should these measures fail, an infusion of an alpha adrenergic blocking agent, e.g., phentolamine mesylate, should be considered.
Excessive elevation of blood pressure and vasoconstriction can occur due to the alpha adrenergic actions of dopamine, especially in patients with a history of occlusive vascular disease. If desired, this condition can be rapidly reversed by dose reduction or discontinuing the infusion, since dopamine has a half-life of less than 2 minutes in the body.
Should these measures fail, an infusion of an alpha adrenergic blocking agent, e.g., phentolamine mesylate, should be considered.
Dopamine at the infusion site can cause local vasoconstriction hence the desirability of infusing into a large vein. The resulting ischaemia can be reversed by infiltration of the affected area with 10-15 ml of saline containing 5 mg to 10 mg phentolamine mesylate. A syringe with a fine hypodermic needle should be used to liberally infiltrate the ischaemic area as soon as extravasation is noted.
Accidental Overdosage:
Accidental overdosage as evidenced by excessive blood pressure elevation can be controlled by dose reduction or discontinuing the dopamine infusion for a short period, since the duration of action of dopamine is short.
Should these measures fail, an infusion of phentolamine mesylate should be considered.
Dofamine should not be used in patients with phaeochromocytoma.
Dofamine should not be used in the presence of uncorrected atrial or ventricular tachyarrhythmias or ventricular fibrillation.
Dopamine should not be used in patients with -
- Hypersensitivity to dopamine or any of the excipients.
- Phaeochromocytoma or hyperthyroidism
Dopamine should not be used in the presence of uncorrected atrial or ventricular tachyarrhythmias or ventricular fibrillation.
Cyclopropane and halogenated hydrocarbon anaesthetics should be avoided.
Dofamine concentrate for solution for infusion, should not be added to any alkaline intravenous solutions, i.e. sodium bicarbonate. Any solution which exhibits physical or chemical incompatibility through a colour change or precipitate should not be administered.
It is suggested that admixtures containing gentamicin sulphate, cephalothin sodium, cephalothin sodium neutral or oxacillin sodium should be avoided unless all other viable alternatives have been exhausted.
Admixtures of ampicillin and Dofamine in 5% glucose solution are alkaline and incompatible and result in decomposition of both drugs. They should not be admixed.
Admixtures of Dofamine, amphotericin B in 5% glucose solution are incompatible as a precipitate forms immediately on mixing.
Iron salts, alkalis or oxidising agents.
Adverse reactions to Dofamine are related to its pharmacological action. The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency.
| More common reactions include | |
| Cardiovascular: | Ectopic heart beats, tachycardia, anginal pain, palpitation, hypotension and vasoconstriction. |
| Gastrointestinal: | Nausea and vomiting. |
| Nervous System: | Headache, anxiety, tremor. |
| Respiratory: | Dyspnea. |
| Renal and urinary disorders: | Polyuria. |
| Investigations: | Serum glucose level increased, BUN level increased. |
| Less common reactions include | |
| Biochemical Abnormalities: | Azotemia. |
| Cardiovascular: | Aberrant conduction, bradycardia, widened QRS complex, hypertension, gangrene, fatal ventricular arrhythmias have been reported on rare occasions. |
| Eye Disorders: | Mydriasis. |
| Nervous System: | Piloerection. |
| Serious or Life-threatening Reactions: | |
| Gangrene of the extremities has occurred following higher doses and in lower doses patients with pre-existing vascular disease. | |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after 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 via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Adverse reactions to dopamine are related to its pharmacological action.
More common reactions include-
Cardiovascular: Ectopic heart beats, tachycardia, anginal pain, palpitation, hypotension, vasoconstriction.
Gastrointestinal: Nausea, vomiting
Nervous System: Headache
Respiratory: Dyspnoea
Less common reactions include-
Biochemical Abnormalities- Azotaemia
Cardiovascular: Aberrant conduction, bradycardia, widened QRS complex, hypertension, gangrene, fatal ventricular arrhythmias have been reported on rare occasions.
Eye Disorders: Mydriasis
Nervous system- Piloerection
Serious or Life-threatening Reactions:
Gangrene of the feet has occurred following doses of 10-14 microgram/kg/min and higher in a few patients with pre-existing vascular disease.
Animal studies have revealed no evidence of teratogenic effects due to Dofamine. However, in one study, administration of Dofamine HCl to pregnant rats resulted in a decreased survival rate of the newborn and a potential for cataract formation in the survivors. Besides this study, there are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.
Dofamine is indicated in adults for the correction of haemodynamic imbalance present in:
- Acute hypotension or shock associated with myocardial infarction, endotoxic septicaemia and trauma.
- As an adjunct after open heart surgery where there is persistent hypotension after correction of hypovolaemia.
- Acute exacerbations of chronic heart failure where is low cardiac output.
For the correction of haemodynamic imbalances in low-perfusion circulatory insufficiency associated with myocardial infarction, trauma, septicaemia, cardiac failure and open heart surgery.
Pharmacotherapeutic group: 3.3 Sympathomimetic, ATC code: C01CA04 Dofamine
Dofamine stimulates adrenergic receptors of the sympathetic nervous system. The drug has principally a direct stimulatory effect on β1-adrenergic receptors, but also appears to have an indirect effect by releasing norepinephrine from its storage sites. Dofamine also appears to act on specific Dofaminergic receptors in the renal, mesenteric, coronary, and intracerebral vascular beds to cause vasodilation. The drug has little or no effect on β2-adrenergic receptors.
In IV doses of 0.5-2 microgram/kg per minute, the drug acts predominantly on Dofaminergic receptors; in IV doses of 2-10 microgram/kg per minute, the drug also stimulates β1-adrenergic receptors. In higher therapeutic doses, α-adrenergic receptors are stimulated and the net effect of the drug is the result of α-adrenergic, β1-adrenergic, and Dofaminergic stimulation. The main effects of Dofamine depend on the dose administered. In low doses, cardiac stimulation and renal vascular dilation occur and in larger doses vasoconstriction occurs. It is believed that α-adrenergic effects result from inhibition of the production of cyclic adenosine -31, 51-monophosphate (cAMP) by inhibition of the enzyme adenyl-cyclase, whereas β-adrenergic effects result from stimulation of adenyl cyclase activity.
Clinical studies showed that the product generally increases systolic and pulse, with no effect or only a slight increase of diastolic pressure. Total peripheral resistance does not usually undergo changes with the administration of low doses of Dofamine or medium. The blood flow in the peripheral vasculature may decrease, whereas the mesenteric blood flow increases. It has also been noted that the product causes dilatation of renal vasculature, which is accompanied by an increase in glomerular filtration rate, renal blood flow and sodium excretion.
Following IV administration, the onset of action of Dofamine occurs within 5 minutes, and the drug has a duration of action of less than 10 minutes.
Dopamine (3,4-dihydroxyphenylethylamine) is the third naturally-occurring catecholamine and is a metabolic precursor of noradrenaline and adrenaline. Dopamine is used therapeutically as the hydrochloride and its main effects are seen in the cardiovascular system and the kidneys.
Heart
Dopamine exerts positive inotropic and chronotropic effects on the myocardium, acting as an agonist at beta-adrenergic receptors. In addition to its direct action on beta-adrenergic receptors, dopamine acts indirectly by releasing noradrenaline from sympathetic storage sites.
Blood Vessesls
Depending on the vascular bed being studied and the dose administered, Dopamine can cause relaxation or contraction of vascular smooth muscle.
Dopamine Receptors
Unlike other endogenous catecholamines or sympathomimetic amines, Dopamine caused vasodilatation in renal, coronary, mesenteric and intracerebral arterial vascular beds in anaesthetised dogs. This vasodilator effect is not antagonised by beta-adrenergic blockers, atropine or antihistamines. However, butyrophenones, phenothiazines, apomorphine and bulbocapnine selectively attenuate dopamine-induced vasodilatation, thus suggesting the existence of specific dopamine vascular receptors similar to those in the basal ganglia and other areas in the central nervous system.
Alpha-adrenergic Receptors
Dose response studies indicate that with a sufficiently large dose, the vasoconstrictor effect of dopamine predominates over its vasodilator effect. This dopamine-induced vasoconstrictor effect is antagonised by alpha-adrenoreceptor blocking agents such as phentolamine and phenoxybenzamine, indicating that vasoconstriction results from the action of dopamine on alpha-adrenergic receptors.
Kidney
Intravenous infusions of dopamine (2.6 to 7.1µg/kg/min.) to seven normal subjects increased estimated average renal plasma flow from 507 to 798ml/min., insulin clearance from 109 to 136ml/min. and average sodium excretion from 171 to 571µEq./min. Although the diuretic and natriuretic effects of dopamine may result from vasodilatation in renal vascular bed (vide supra), disassociation between natriuresis and increments in renal blood flow has been observed, suggesting that other mechanisms such as redistribution of intrarenal blood flow may be involved.
5.2 Pharmacokinetic properties
Absorption
Following IV administration the maximum plasma concentration is reached within a few minutes.
Distribution
The drug is widely distributed in the body but does not cross the blood-brain barrier to a substantial extent. It is not known if Dofamine crosses the placenta.
Biotransformation
Dofamine is metabolised in the liver, kidneys, and plasma by monoamine oxidase (MAO) and catechol-0-methyltransferase (COMT) to the inactive compounds homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid. In patients receiving MAO inhibitors, the duration of action of Dofamine may be as long as 1 hour. About 25% of a dose of Dofamine is metabolised to norepinephrine within the adrenergic nerve terminals.
Elimination
Dofamine has a plasma half-life of about 2 minutes. Dofamine is excreted in urine principally as HVA and its sulphate and glucuroide conjugates and as 3,4-dihydroxyphenylacetic acid. A very small fraction of a dose is excreted unchanged. Following administration of radio labelled Dofamine, approximately 80% of the radioactivity reportedly is excreted in urine within 24 hours.
Dopamine is inactive when taken orally and its vasoconstrictor properties preclude its administration by subcutaneous or intramuscular injection. Dofamine is administered by intravenous infusion.
Dopamine is a metabolic precursor of nor-adrenaline and, whereas a proportion is excreted as the metabolic products of nor-adrenaline, the majority is mainly metabolised into 3,4,-Dihydroxyphenylacetic Acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic (HVA) which are rapidly excreted in the urine.
The plasma half-life of dopamine is approximately two minutes.
Dofamine should not be used in patients with hyperthroidism.
Cyclopropane and halogenated hydrocarbon anaesthetics should be avoided.
Dofamine should be used with caution in patients with narrow angle glaucoma.
Dofamine should be used with caution in patients with benign prostatic hyperplasia with urinary retention.
Patients who have been treated with MAO inhibitors prior to Dofamine should be given reduced doses; the starting dose should be one tenth (1/10) of the usual dose.
Excess administration of potassium-free solutions may result in significant hypokalaemia.
The intravenous administration of these solutions can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary oedema.
Dofamine hydrochloride should not be added to sodium bicarbonate or other alkaline solution as drug inactivation will occur.
Conditions like hypoxia, hypercapnia and acidosis can reduce Dofamine efficacy and/or increase the incidence of adverse events and should therefore identified and corrected before or during administration of Dofamine hydrochloride.
Regular clinical and biochemical assessment is necessary to monitor changes in fluid, electrolyte or acid-base status during prolonged treatment and whenever the patient condition demands it. During treatment with Dofamine hydrochloride, blood pressure, heart rate, urine output, EKG and cardiac output should be monitored.
If tachyarrhythmias or increase in ectopic beats are observed, Dofamine hydrochloride should be reduced, if possible.
Hypovolaemia should be corrected where necessary prior to Dofamine infusion. Low doses should be used in shock due to acute myocardial infarction.
If a disproportionate rise in diastolic pressure (i.e. a marked decrease in pulse pressure) is observed, the infusion rate should be decreased and the patients observed carefully for further evidence of predominant vasoconstriction activity, unless such an effect is desired.
Patients with a history of peripheral vascular disease should be closely monitored for any changes in colour or temperature of the skin of the extremities. If change of skin colour or temperature occurs and is thought to be the result of compromised circulation to the extremities, the benefits of continued Dofamine infusion should be weighed against the risk of possible necrosis. These changes may be reversed by decreasing the rate or discontinuing the infusion.
Dofamine hydrochloride should be infused into a large vein whenever possible to prevent the possibility of infiltration of perivascular tissue adjacent to the infusion site. Extravasation may cause necrosis and sloughing of the surrounding tissue. Ischaemia can be reversed by infiltration of the affected area with 10-15 ml of saline containing 5 to 10 mg phentolamine mesylate. A syringe with a fine hypodermic needle should be used to liberally infiltrate the ischaemic area as soon as extravasation is noted.
Dofamine should be used with extreme caution in patients inhaling cyclopropane or halogenated hydrocarbon anaesthetics due to the arrhythmogenic potential.
Dextrose solutions should be used with caution in patients with known subclinical or overt diabetes mellitus.
As the effect of Dofamine on impaired renal and hepatic function is not known, close monitoring is advised.
Dofamine infusion should be withdrawn gradually, to avoid unnecessary hypotension.
Dofamine hydrochloride, concentrate for solution for infusion, contains sodium metabisulfite, excipient that can cause allergic reactions including anaphylactic symptoms and life-threatening, or episodes of less severe asthma, in susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. This sensitivity is seen more frequently in asthmatic population than in non-asthmatic.
This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially 'sodium-free'.
The solution contains an antioxidant, sodium metabisulphite, a sulphite that may cause hypersensitivity reactions including bronchospasm, anaphylaxis and life-threatening episodes in certain susceptible individuals. The prevalence of sulphite-sensitivity in the general population is unknown and is probably low. Sulphite-sensitivity is seen more frequently in persons with a history of asthma or atopic allergy.
Each ampoule of this injection contains 2.42 mg sodium per ml.
Patients who have been treated with MAO inhibitors prior to dopamine should be given reduced doses; the starting dose should be one tenth (1/10th) of the usual dose.
Excess administration of potassium-free solutions may result in significant hypokalaemia.
The intravenous administration of these solutions can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary oedema.
Precautions:
Hypovolaemia should be corrected where necessary prior to dopamine infusion. Low doses should be used in shock due to acute myocardial infarction.
If a disproportionate rise in diastolic pressure (i.e. a marked decrease in pulse pressure) is observed, the infusion rate should be decreased and the patients observed carefully for further evidence of predominant vasoconstriction activity, unless such an effect is desired.
Patients with a history of peripheral vascular disease should be closely monitored for any changes in colour or temperature of the skin of the extremities. If change of skin colour or temperature occurs and is thought to be the result of compromised circulation to the extremities, the benefits of continued dopamine infusion should be weighed against the risk of possible necrosis. These changes may be reversed by decreasing the rate or discontinuing the infusion. IV administration of phentolamine mesylate 5-10 mg may reverse the ischaemia.
Dofamine in 5% glucose injection should be infused into a large vein whenever possible to prevent the possibility of infiltration of perivascular tissue adjacent to the infusion site. Extravasation of Dofamine during infusion may cause ischaemic necrosis and sloughing of surrounding tissue. Ischaemia can be reversed by infiltration of the affected area with 10-15 ml of saline containing 5 to 10 mg phentolamine mesylate. A syringe with a fine hypodermic needle should be used to liberally infiltrate the ischaemic area as soon as extravasation is noted.
Administration of Dofamine should always be under the direct supervision of a physician to whom facilities are available for monitoring cardiovascular and renal indices, including blood volume, cardiac output, blood pressure, electrocardiography and urine flow.
Glucose solutions should be used with caution in patients with known subclinical or overt diabetes mellitus.
When dopamine is used in patients with a history of occlusive vascular disease, particular attention should be paid to the status of blood circulation in the extremities.
The occurrence of undesirable increases in blood pressure or vasoconstriction or decrease in urinary output requires a reduction in dosage of Dofamine.
The routine use of low-dose Dofamine in critically ill patients to prevent or treat acute renal failure is not recommended because this may cause adverse effects which could further compromise such patients.
As the effect of dopamine on impaired renal and hepatic function is not known, close monitoring is advised.
Dopamine infusion should be withdrawn gradually, to avoid unnecessary hypotension.
Not applicable, as the drug product is to be administered at the hospital.
Not applicable in view of the indications for use and the short half-life of the drug.
Posology
Adults
Where appropriate, the circulating blood volume must be restored with a suitable plasma expander or whole blood, prior to administration of Dofamine hydrochloride.
Begin infusion of Dofamine hydrochloride solution at doses of 2.5 microgram/kg/min in patients who are likely to respond to modest increments of heart force and renal perfusion.
In more severe cases, administration may be initiated at a rate of 5 microgram/kg/min and increased gradually in 5 to 10 microgram/kg/min increments up to 20 to 50 microgram/kg/min as needed. If doses in excess of 50 microgram/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 Dofamine dosage should be considered. It has been found that more than 50% of patients have been satisfactorily maintained on doses less than 20 microgram/kg/min.
In patients who do not respond to these doses, additional increments of Dofamine may be given in an effort to achieve adequate blood pressure, urine flow and perfusion generally.
Treatment of all patients requires constant evaluation of therapy in terms of blood volume, augmentation of cardiac contractility, and distribution of peripheral perfusion and urinary output.
Dosage of Dofamine should be adjusted according to the patient's response, with particular attention to diminution of established urine flow rate, increasing tachycardia or development of new dysrhythmias as indications for decreasing or temporarily suspending the dosage.
Patients who have been treated with MAO inhibitors 2-3 weeks prior to administration of Dofamine require a substantially reduced dosage. (The starting dose should be reduced to at least 1/10 of the usual dose.
Paediatric population
The safety and efficacy of Dofamine in paediatric patients has not been established.
Elderly
In clinical trials with parenteral Dofamine, the number of patients aged 65 years or older included was not sufficient to determine if they behave differently from younger patients. Generally, dose selection in elderly patients should be cautious and an initial lower dose is regularly used.
Close monitoring is suggested for blood pressure, urine flow and peripheral tissue perfusion.
Method of administration:
To be administered by intravenous infusion only after dilution with the appropriate diluents.
Dofamine hydrochloride should be infused into a large vein whenever possible, preferably with an infusion syringe pump system. Special care should be given to the perfusion rate in order to avoid inadvertent boluses.
The solution must be diluted before administration. Alkaline solutions such as 5% sodium bicarbonate should NOT be added to Dofamine because the drug will be inactivated. The usual dilution is 1,600 micrograms per ml and this may be achieved by transfer, aseptically of 800mg of Dofamine to one of the following sterile I.V. solutions: -
Sodium Chloride Injection
5% Glucose Injection
5% Glucose and 0.9% Sodium Chloride Injection
5% Glucose and 0.45% Sodium Chloride Solution
5% Glucose in Ringer Lactate Solution
Sodium Lactate 1/6 Molar Injection
Lactated Ringer's Injection
A suitable metering device is required in the infusion system to control the rate of flow, and this should be adjusted to the optimum patient response and monitored constantly in the light of the individual patient's response.
Adults: Use as large a vein as possible for infusion. The initial rate of infusion is 2 to 5 micrograms per kilogram bodyweight per minute and this may be increased gradually by increments of 5 to 10 micrograms/kg/minute until the optimum dose for the individual is achieved. Up to 50 micrograms/kg/minute may be required, and even higher doses have been used.
Children: The safety and efficacy of Dofamine therapy in children have not been established.
For single use.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Parenteral drug products should be visually inspected for particulate matter and discolouration prior to administration. Do not use if the injection is darker than slightly yellow or discoloured in any other way.
Preparation of Infusion Solutions
Suggested Dilution
Aseptically transfer the sterile concentrate for solution for infusion into the IV solution as shown in the following table:
| Strength of Concentrate (mg/ml) | Volume of concentrate (ml) | Volume of IV Solution (ml) | Final Concentration (microgram/ml) |
| 40 mg/ml | 5 | 500 | 400 |
| 40 mg/ml | 5 | 250 | 800 |
Dofamine hydrochloride can be diluted with:
- 0.9% Sodium Chloride Injection
- 5% Glucose Injection
- 5% Glucose and 0.9% Sodium Chloride Injection
- 0.45% Sodium Chloride Solution
- 5% Glucose and 0.45% Sodium Chloride Solution
- 5% Glucose in Ringer Lactate Solution
- Sodium Lactate 1/6 Molar Injection
- Lactated Ringer's Injection
This solution must be diluted before use.
Do not dilute with alkaline solution.
Do not use the injection if it is darker than slightly yellow or discoloured in any other way.
For the preparation of Dofamine Intravenous Infusion.
Use as directed by the physician.
Keep out of reach of children.
