Norepinephrine Bitartrate 4mg IV Injection: Full Prescribing Information..

 EPINOR

Norepinephrine / Noradrenaline Bitartrate 8 mg

(equiv noradrenaline base 4mg)

4 ml Injection for I.V. Use

 

Presentation

Epinor is supplied in 4ml ampoules. Each ampoule contains 4mg of noradrenaline base as the acid tartrate. Each ml contains an equivalent of Img noradrenaline base, sodium chloride for isotonic, and not more than 4 mg of sodium metabisulfite as an antioxidant with a pH of 3 to 4.5. Epinor is supplied as a clear sterile solution, designed for intravenous infusion

 

Mechanism of Action

Noradrenaline (sometimes referred to as norepinephrine or 1-arterenol/levarterenol) is a sympathomimetic amine, which differs from adrenaline by the absence of a methyl group on the nitrogen atom. Noradrenaline functions as a peripheral vasoconstrictor (alpha-adrenergic action), an inotropic heart stimulator, and a dilator of coronary arteries (beta-adrenergic action). These actions result in a usually increases aortic blood pressure, coronary artery blood flow, and myocardial oxygenation, thereby helping to limit the area rate and rhythm than in the hypotensive state, in hypotension that persists after correction of blood volume deficits, Epinor help raise the blood pressure to an optimal level and establish a more adequate circulation.

 

Pharmacokinetics

 

Absorption

Orally ingested noradrenaline is destroyed in the Gl tract, and the drug is poorly absorbed after subcutaneous injection. After IV administration, a pressor response occurs rapidly. The drug has a short duration of action, and the pressor action stops within 1-2 minutes after the infusion is discontinued.

 

Distribution

Noradrenaline localizes mainly in sympathetic nervous tissue. The drug crosses the placenta but not the blood-brain barrier.

 

Elimination

The pharmacological actions of noradrenaline are determined primarily by uptake and metabolism in sympathetic nerve endings. The drug is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO). The major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenyl glycol, 3, 4 4-dihydroxymandelic acid, and 3, 4 4-dihydroxyphenylglycol. Noradrenaline metabolites are excreted in urine primarily as the sulfate conjugates, to a lesser extent, as the glucuronide conjugates. Only small quantities of noradrenaline are excreted unchanged

 

Indications

For the restoration of blood pressure in certain acute hypotensive states (e.g., pheochromocytoma, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion, and drug reactions). As an adjunct in the treatment of cardiac arrest. To restore and maintain an adequate blood pressure after an effective heartbeat and ventilation have been established by other means.

 

Dosage and Administration

Noradrenaline as the acid tartrate. It is a concentrated, potent drug that must be diluted in dextrose dextrose-containing solution before infusion. An infusion of noradrenaline should be given into the large vein (see warning and precautions). Restoration of Blood Pressure in Acute Hypotensive States. Blood volume depletion should always be corrected as fully as possible before any vasopressor is administered. When, as an emergency measure, intra-aortic pressures must be maintained to prevent cerebral or coronary artery ischemia, nor adrenaline can be administered before and concurrently with blood volume replacement

 

Diluents

Epinor should be diluted in five percent (5%) dextrose injection or five percent (5%) dextrose and sodium chloride injections. These dextrose-containing fluids provide protection against significant loss of potency due to oxidation. Administration in saline (for example, by use of a Y-tube and individual containers if given simultaneously)

 

Average Dosage

Add an ampoule (4ml.) of Epinor 1:1000 (4mg of noradrenaline) to 1,000ml of a 5% dextrose containing solution. Each ml of this dilution contains 4 mcg of the base of noradrenaline (or 8 mcg of the acid tartrate). Give this solution by intravenous infusion. Insert a plastic intravenous catheter through a suitable bore needle well advanced centrally into the vein and securely fixed with adhesive tape, avoiding, if possible, a catheter tie-in technique as this promotes stasis An I.V. drip chamber or other suitable metering device is essential to permit an accurate estimation of the rate of flow in drops per minute.

After observing the response to an initial dose of 2 mL to 3 mL. (form 8mcg to 12mcg of base) per minute, adjust the rate of flow to establish and maintain a low normal blood pressure (usually 80 mmHg to 100 mmHg systolic) sufficient to maintain the circulation to vital organs, in previously hypertensive patients, it is recommended that the blood pressure should be raised no higher than 40 mmHg below the pre-existing systolic pressure, the average maintenance dose ranges from 0.5ml to 1ml per minute (form 2meg to 4mcg of base).

 Learn About : Common Drug Interactions and Contraindications Every Doctor Should Know. 

High Dosage

Great individual variation occurs in the dose required to attain and maintain an adequate blood pressure. In all cases, the dosage of noradrenaline should be titrated according to the response of the patient. Occasionally, much larger or even enormous daily doses (as high as 68mg base or 17 ampoules) may be necessary if the patient remains hypotensive, but occult blood volume depletion should always be suspected and corrected when present. Central venous pressure monitoring is usually helpful in detecting and treating these situations.

 

Fluid Intake

The degree of dilution depends on clinical fluid volume requirements. If large volumes of fluid (dextrose) are needed at a flow rate that would involve an excessive dose of the pressure agent per unit of time, a solution more dilute than 4mcg per ml should be used, on the other hand, when large volumes of fluid are clinically undesirable, a concentration greater than 4mcg per ml may be necessary.

 

Duration of Therapy

The infusion should be continued until adequate blood pressure and tissue perfusion are maintained without therapy. Infusions of noradrenaline should be reduced gradually, avoiding abrupt withdrawal. In some of the reported cases of vascular collapse due to acute myocardial infarction, treatment was required for up to six days.

 

Adjunctive Treatment in Cardiac Arrest

Infusions of noradrenaline are usually administered intravenously during cardiac resuscitation to restore and maintain an adequate blood pressure after an effective heartbeat and ventilation have been established by other means. [Noradrenaline's powerful beta-adrenergic stimulating action is also thought to increase the strength and effectiveness of systolic contractions once they occur.]

 Read About : Meningococcal Vaccine (Menactra): Effectiveness, Safety & Who Needs It?

Average Dosage

To maintain systemic blood pressure during cardiac arrest management, noradrenaline is used in the same manner described under Restoration of Blood Pressure in Acute Hypotensive States. Parenteral drug products should be inspected visually for particulate matter and discoloration before use, whenever the solution and container permit. Do not use the solution if its colour is pinkish or darker than slightly yellow or if it contains a precipitate. Avoid contact with iron salts, alkalis, or oxidizing agents.

 

Contraindications

Noradrenaline should not be given to patients who are hypotensive from blood volume deficits except as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed. If noradrenaline is administered to maintain blood pressure in the absence of blood volume replacement, the following may occur: severe peripheral and visceral vasoconstriction, decreased renal perfusion and urine output, poor systemic blood flow despite "normal" blood pressure, tissue hypoxia, and lactic acidosis. Noradrenaline should also not be given to patients with mesenteric or peripheral vascular thrombosis (because of the risk of administration of increasing ischemia and extending the area of infarction unless, in the opinion of the attending physician, the administration of noradrenaline is necessary as a life-saving procedure. Cyclopropane and balothane anesthetics increase cardiac autonomic irritability and therefore seem to sensitize the myocardium to the action of intravenously administered adrenaline or noradrenaline. Hence, the use of noradrenaline during Cyclopropane and halothane anaesthesia is generally considered contraindicated because of the risk of producing ventricular tachycardia or fibrillation. The same type of cardiac arrhythmias may result from the use of noradrenaline in patients with profound hypoxia or hypercarbia.

 

Warnings and precautions

 

Warnings

Noradrenaline should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe, prolonged hypertension may result. Epinor 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. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

 Find creatinine clearance using an online creatinine clearance calculator. 

Precautions

 

General:

Avoid Hypertension

Because of the potency of noradrenaline and because of varying response to pressor substances, the possibility always exists that dangerously high blood pressure may be produced on the overdoses of this pressor agent. It is desirable, therefore, to record the blood pressure every two minutes from the time administration is started until the desired blood pressure is obtained, then every five minutes if administration is to be continued. The rate of drip must be watched constantly, and the patient should never be left unattended while receiving noradrenaline. A headache may be a symptom of hypertension due to overdosing.

 Read : Atracurium Besylate (Acuron injection): Complete Guide for Anesthesia and ICU Use.

Site of Infusion

Whenever possible, infusions of noradrenaline should be given into a large vein, particularly an antecubital vein because, when administered into this vein, the risk of necrosis of the overlying skin from prolonged vasoconstriction is apparently very slight. Some authors have indicated that the femoral vein is also an acceptable route of administration. Catheter tie-in technique should be avoided; if possible, since the obstruction to blood around the tubing may cause stasis and increased local concentration of noradrenaline. Occlusive vascular diseases (for example, atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger's disease) are more likely to occur in the lower than in the upper extremity. Therefore, one should avoid the veins of the leg in elderly patients or in those suffering from such disorders. Gangrene has been reported in a lower extremity when infusions of noradrenaline were given in an ankle vein.

 

Extravasation

The infusion site should be checked frequently. Care should be taken to avoid extravasation of noradrenaline into the tissues, as local necrosis might ensure due to the vasoconstrictive action of the drug. Blanching along the course of the infused vein, sometimes without obvious extravasation, has been attributed to vasoconstriction with increased permeability of the vein wall, permitting some leakage. This also may progress on rare occasions to super-cial slough, particularly during infusion into leg veins in elderly patients or in those suffering from obliterative vascular disease. Hence, if blanching occurs, consideration should be given to the advisability of changing the infusion site at intervals to allow the effects of local vasoconstriction to subside.

 

IMPORTANT - Antidote for Extravasation Ischemia

To prevent sloughing and necrosis in areas in which extravasation has taken place, the area should be infiltrated as soon as possible with 10ml to 15ml of saline solution containing from 5mg to 10mg of phentolamine, an adrenergic blocking agent. A syringe with a one hypodermic needle should be used; with the solution being interacted liberally throughout the area, which is easily identified by its cold, hard and pailed appearance. Sympathetic blockage with phentolamine causes immediate and conspicuous local hyperaemic changes if the area is in-ltrated within 12 hours. Therefore, phentolamine should be given as soon as possible after the extravasation is noted.

 

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been performed.

 

Pregnancy

Category A

Animal reproduction studies have not been conducted with noradrenaline. It is also not known whether noradrenaline can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Noradrenaline should be given to a pregnant woman only if clearly needed.

 

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when noradrenaline is administered to a nursing woman.

 

Paediatric Use

Safety and effectiveness in paediatric patients has not been established.

 

Geriatric Use

Clinical studies of noradrenaline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Although clinical experience has not indented differences in responses between the elderly and younger patients, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapy.

Noradrenaline infusions should not be administered into the veins in the leg in elderly patients (see precautions, General)

 Read about : Peptic Ulcer: Causes, Symptoms, and Treatment

Adverse Events

The following reactions can occur:

 

Body as A Whole

Ischaemic injury due to potent vasoconstrictor action and tissue hypoxia

Cardiovascular System

Bradycardia, probably as a reflex result of a rise in blood pressure, arrhythmias.

Nervous System

Anxiety, transient headache

Respiratory System

Respiratory difficulty

Skin and Appendages

Extravasation necrosis at injection site, Prolonged administration of any potent vasopressor may result in plasma volume depletion which should be continuously corrected by appropriate fluid and electrolyte replacement therapy. If plasma volumes are not corrected, hypotension may recur when noradrenaline is discontinued, or blood pressure may be maintained at the risk of severe peripheral and visceral vasoconstriction (e.g. decreased renal perfusion) with diminution in blood flow and tissue perfusion with subsequent tissue hypoxia and lactic acidosis and possible ischaemic injury. Gangrene of extremities has been rarely reported.

 

Overdoses or conventional doses in hypersensitive persons(e.g. hyperthyroid patients) cause severe hypertension with violent headache, photophobia, stabbing retrosternal pain, pallor, intense sweating and vomiting.

 

Interactions

Cyclopropane and halothane anaesthetics increase cardiac autonomic irritability and therefore seem to sensitive the myocardium to the action of intravenously administered adrenaline or noradrenaline. Hence, the use of noradrenaline during Cyclopropane and halothane anaesthesia is generally considered contraindicated because of the risk of producing ventricular tachycardia or fibrillation. The same type of cardiac arrhythmias may result from the use of noradrenaline in patients with profound hypoxia or hypercardia.

 

Noradrenaline should be used with extreme caution in patients receiving monoamine oxidase inhibitor (MAOI) or antidepressants of the triptyline or imipramine types, because severe, prolonged hypertension may result. Epinor infusion solutions should not be mixed with other drugs. Infusion solutions containing noradrenaline acid tartrate have been reported to be incompatible with alkalies and oxidizing agents, barbiturates, chlorpheniramine, chlorothiazide, nitrofurantion, phenytoin, sodium bicarbonate, sodium iodide, streptomycin, sulfadiazine and sulfafurazole.

 

Over dosage

Over dosage with noradrenaline may result in headache, severe hypertension reflex bradycardia, marked increase in peripheral resistance and decreased cardiac output, In case of accidental over dosage, as evidenced by excessive blood pressure elevation, discontinued noradrenaline until the condition of the patient stabilizes.

 

Pharmaceutical precautions

 

Protect from heat and light

Store at 15°C to 25°C

Keep out of the reach of children. Medicine classification: Do not use if solution is brown. Prescription Medicine: As directed by the physician.

 

Package Quantities

4ml x 10 Ampoules in outer unit carton box.

Each 4ml ampoule contains 8mg noradrenaline bitartrate is equivalent 4mg noradrenaline.