NOREPRESS Injection 4 mg/4 ml

Norepinephrine bitartrate monohydrate

Category:

COMPOSITION :

Norepress® Injection 4 mg/4 ml, each ml contains : Norepinephrine bitartrate monohydrate equivalent to Norepinephrine 1 mg.

PHARMACOLOGY :

Norepinephrine is a sympathomimetic amine which differs from Epinephrine by the absence of methyl group on the nitrogen atom. Norepinephrine bitartrate functions as a peripheral vasoconstrictor (α-adrenergic action) and as inotropic stimulator of the heart and dilator of coronary arteries (β- adrenergic action).

INDICATIONS :

  • For blood pressure control in certain acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion and drug reactions).
  • As an adjunct in the treatment of cardiac arrest and profound

DOSAGE AND ADMINISTRATIONS :

Norepress® Injection is a concentrated and potent drug which must be diluted in Dextrose-containing solutions prior to infusion. An infusion of Norepress® should be given into a large vein.

Restoration of Blood Pressure in Acute Hypotensive State

  • Blood volume depletion should always be corrected as fully as possible before any vasopressor is When, as an emergency measure, intra-aortic pressure must be maintained to prevent cerebral or coronary artery ischemia, Norepress® may be given before and concurrently with blood volume replacement.
  • Diluent

Norepress® should be diluted in 5% Dextrose injection or 5% Dextrose and Sodium chloride injections. This Dextrose-containing solution are protection against significant loss of potency due to oxidation. Administration in saline solution alone is not recommended. Whole blood or plasma, if indicated to increase blood volume, should be administered separately (e.g., by use of a Y-tube and individual containers if given simultaneously).

  • Average Dosage

Add the content of the ampoule (4 mg/4 ml) of Norepinephrine Bitartrate Monohydrate to 1000 ml of a 5% Dextrose-containing solution. Each ml of this dilution contains 4 mcg of Norepinephrine base. Give this solution by IV infusion. Insert a plastic IV catheter through a suitable bore needle well advanced centrally into the vein then fixed with adhesive tape, avoiding, if possible, a catheter tie-in technique as this promotes stasis. An IV 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 – 3 ml (from 8 – 12 mcg of base) per minute, adjust the rate of flow to establish and to maintain a low normal blood pressure (usually 80 – 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 range from 0.5 – 1 ml/minute (2 – 4 mcg of base form).

  • High Dosage

Great individual variation occurs in the dose required to attain and maintain an adequate blood pressure. In all cases, dosage of Norepress® should be titrated according to the response of the patient. Occasionally, much larger or even enormous daily dose (as high as 68 mg base or 17 ampoules) may be necessary if patients 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 this situation.

  • Fluid Intake

The degree of dilution depends on clinical fluid volume requirements. If large volume of fluid (Dextrose) is needed at a flow rate that would involve an excessive dose of the pressor agent per unit of time, a solution more dilute than 4 mcg/ml should be used. On the other hand, when large volumes of fluid are clinically undesirable, a concentration greater than 4 mcg/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 Norepress® 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 6 days.

Adjunctive Treatment in Cardiac Arrest

  • Infusions of Norepress® are usually administered IV during cardiac resuscitation to restore and maintain an adequate blood pressure after an effective heartbeat and ventilation have been established by other [Norepress®’s powerful β-adrenergic stimulating action is also thought to increase the strength and effectiveness of systolic contractions once they occur].
  • Average Dosage

To maintain systemic blood pressure during the management of cardiac arrest, Norepress® is used in the same manner as described under Restoration of Blood Pressure in Acute Hypotensive States.Parenteral drug products should be visually observed for any particulate matter and discoloration prior to use, whenever 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.

INCOMPATIBILITY :

Incompatible with alkalis and oxidizing agents, Barbiturates, Chlorphenamine, Chlorothiazide, Nitrofurantoin, Novobiocin, Phenytoin, Sodium bicarbonate, Sodium iodide and Streptomycin.

Incompatibility with insulin has also been reported.

OVERDOSAGE :

Overdosage of Norepinephrine 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, discontinue Norepinephrine until the condition of the patient stabilized.

CONTRAINDICATIONS :

Norepinephrine should not be given in hypotensive patients 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 Norepinephrine is continuously administered to maintain blood pressure in the absence of blood replacement, the following conditions may occur : Severe peripheral and visceral vasoconstriction, decreased renal perfusion and urine output, poor systemic blood flow despite normal blood pressure, tissue hypoxia and lactate acidosis.

Norepinephrine should also not be given to patients with mesenteric or peripheral vascular thrombosis (because of the risk of increasing ischaemia and extending the area of infarction) unless, in the opinion of the attending physician, the administration of Norepinephrine is necessary as a life-saving procedure.

Cyclopropane and Halothane anaesthetics increase cardiac autonomic irritability and therefore seem to sensitize the myocardium to the action of intravenously administered Epinephrine or Norepinephrine. Hence, the use of Norepinephrine during the administration of Cyclopropane and Halothane anesthesia is generally considered contraindicated because of the risk of producing ventricular tachycardia or fibrilation.

The same type of cardiac arrhythmias may result from the use of Norepinephrine in patients with profound hypoxia or hypercarbia.

WARNINGS AND PRECAUTIONS :

Warnings

Norepinephrine should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOIs) or antidepressants of the Triptyline or Imipramine type, because severe, prolonged hypertension may result.

Norepinephrine bitartrate 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.

Precautions

  • Avoid Hypertension

Because of the potency of Norepinephrine and because of varying response to pressor substances, the possibility always exists that dangerously high blood pressure may be produced with overdoses of this pressor agent. Therefore, to record the blood pressure every two minutes from the time administration is started until the desired blood pressure is obtained, then every 5 minutes if administration is to be continued. The rate of flow must be watched constantly and the patient should never be left unattended while receiving Norepinephrine. Headache may be a symptom of hypertension due to overdosage.

  • Site of Infusion

Whenever possible, infusions of Norepinephrine 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. A catheter tie-in technique should be avoided, if possible, since the obstruction to blood flow around the tubing may cause stasis and increased local concentration of the drug. Occlusive vascular diseases (e.g., 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 infusion of Norepinephrine were given in an ankle vein.

  • Extravasation

The infusion site should be checked frequently for free flow. Care should be taken to avoid extravasation of Norepinephrine into the tissue, as local necrosis might ensue due to the vasoconstrictive action of the drug. Blanching along the course of the infused vein, sometimes without obvious extravasation, has been attributed to vasa vasorum constriction with increased permeability of the vein wall, permitting some leakage.

This also may progress on rare occasions to superficial 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 Ischaemia

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

  • Carcinogenicity,Mutagenicity and Impairment of Fertility : Studies have not been
  • Pregnancy: Category  Animal reproduction studies have not been conducted with Norepinephrine. It is also not known whether Norepinephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Norepinephrine 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 manydrugs are excreted in human milk, caution should be exercised when Norepinephrine is administered to a nursing
  • PediatricUse : Safety and effectiveness in pediatric patients have not been
  • GeriatricUse : Clinical studies of Norepinephrine did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patients should be cautious, usually starting at the low-end of dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other therapy. Norepinephrine infusions should not be administered into the veins in the leg in elderly

DRUG INTERACTIONS :

  • Cyclopropane and Halothane anesthetics increase cardiac autonomic irritability and therefore seemto sensitize the myocardium to the action of intravenously administered Epinephrine or  Hence, the use of Norepinephrine during Cyclopropane and Halothane anesthesia 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 Norepinephrine in patients with profound hypoxia or hypercarbia.
  • Norepinephrine should be used with extreme caution in patients receiving monoamine oxidaseinhibitors (MAOIs) or antidepressants of the Triptyline or Imipramine types, because severe, prolonged hypertension may

ADVERSE REACTIONS :

  • Bodyas A Whole : Ischemic injury due to potent vasoconstrictor action and tissue
  • CardiovascularSystem : Bradycardia, probably as a reflex result of a rise in blood pressure,
  • NervousSystem : Anxiety, transient headache.
  • RespiratorySystem : Respiratory
  • Skinand Appendages : Extravasation necrosis at injection
  • Prolonged administration of any potent vasopressor may result in plasma volume depletion whichshould be continuously corrected by appropriate fluid and electrolyte replacement  If plasma volumes are not corrected, hypotension may recur when Norepinephrine 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.
  • Overdosesor conventional doses in hypersensitive persons (e.g., hyperthyroid patients) cause severe hypertension with violent headache, photophobia, stabbing retrosternal pain, pallor, intense sweating and vomiting.

PRESENTATIONS :

Norepress® Injection 4 mg/4 ml is available in the form of a clear solution, colourless and free from foreign matter, packaged in :

Box, 5 ampoules @ 4 ml

List of Excipients :

Sodium chloride, sodium metabisulfite dan water for injection.

STORAGE :

STORE BELOW 25ºC AND DRY PLACE, PROTECT FROM LIGHT

The diluted solution in 5% Dextrose and 5% Dextrose + 0.9% Sodium Chloride is stable for 24 hours at 25°C. The injections should not be used if it is reddish or darker than light yellow or a precipitate forms.

ON MEDICAL PRESCRIPTION ONLY

 

Manufactured by :

BERNOFARM

Sidoarjo – Indonesia