Indications : התוויות

4. INDICATIONS AND USAGE
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 hypotension.

5. DESCRIPTION
Noradrenaline (norepinephrine, sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a sympathomimetic amine which differs from epinephrine by the absence of a methyl group on the nitrogen atom.
Norepinephrine Bitartrate is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate and has the following structural formula:



NORADRENALINE SINTETICA is supplied in sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion following dilution. Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Each mL contains 2 mg noradrenaline bitartrate, the equivalent of 1 mg base of noradrenaline, sodium chloride for isotonicity, and water for injection. It has a pH of 3 to 4.5. The air in the ampoules has been displaced by nitrogen gas.

CLINICAL PHARMACOLOGY
NORADRENALINE SINTETICA functions as a peripheral vasoconstrictor (alpha-adrenergic action) and as an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action).

6. CONTRAINDICATIONS
NORADRENALINE SINTETICA should not be given to patients with hypersensitivity to the active substance or to any of the excipients listed in section 5.
NORADRENALINE SINTETICA 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 SINTETICA is continuously 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 lactate acidosis.
NORADRENALINE SINTETICA should also not be given to patients with mesenteric or peripheral vascular thrombosis (because of the risk of increasing ischemia and extending the area of infarction) unless, in the opinion of the attending physician, the administration of NORADRENALINE SINTETICA is necessary as a life-saving procedure.
Cyclopropane and halothane anesthetics increase cardiac autonomic irritability and therefore seem to sensitize the myocardium to the action of intravenously administered epinephrine or norepinephrine. Hence, the use of NORADRENALINE SINTETICA 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 NORADRENALINE SINTETICA in patients with profound hypoxia or hypercarbia.


7. WARNINGS
NORADRENALINE SINTETICA 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.
PRECAUTIONS
General
Avoid Hypertension: Because of the potency of NORADRENALINE SINTETICA 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. 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 flow must be watched constantly, and the patient should never be left unattended while receiving NORADRENALINE SINTETICA. Headache may be a symptom of hypertension due to overdosage.
Site of Infusion: Whenever possible, infusions of NORADRENALINE SINTETICA 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 (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 SINTETICA 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 NORADRENALINE SINTETICA into the tissues, 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 Ischemia: To prevent sloughing and necrosis in areas in which extravasation has taken place, the area should be infiltrated as soon as possible with 10 mL to 15 mL of saline solution containing from 5 mg to 10 mg of phentolamine, 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 hyperemic changes if the area is infiltrated within 12 hours. Therefore, phentolamine should be given as soon as possible after the extravasation is noted.

This medicinal product contains less than 1 mmol (23 mg) sodium per ampoule, i.e. it is essentially “sodium free”.

Drug Interactions
Cyclopropane and halothane anesthetics increase cardiac autonomic irritability and therefore seem to sensitize the myocardium to the action of intravenously administered epinephrine or norepinephrine. Hence, the use of NORADRENALINE SINTETICA 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 NORADRENALINE SINTETICA in patients with profound hypoxia or hypercarbia.
NORADRENALINE SINTETICA 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed.
Pregnancy: Animal reproduction studies have not been conducted with NORADRENALINE SINTETICA. It is also not known whether NORADRENALINE SINTETICA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. NORADRENALINE SINTETICA 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 SINTETICA is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

Geriatric Use
Clinical studies of NORADRENALINE SINTETICA 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 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 drug therapy.
NORADRENALINE SINTETICA infusions should not be administered into the veins in the leg in elderly patients (see PRECAUTIONS, General).

8. ADVERSE REACTIONS
The following reactions can occur:
Body As A Whole: Ischemic injury due to potent vasoconstrictor action and tissue hypoxia.
Cardiovascular System: Bradycardia, probably as a reflex result of a rise in blood pressure, arrhythmias and stress cardiomyopathy.
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 SINTETICA 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 ischemic 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.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form (https://sideeffects.health.gov.il)
OVERDOSAGE
Overdosage with NORADRENALINE SINTETICA may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output. In case of accidental overdosage, as evidenced by excessive blood pressure elevation, discontinue NORADRENALINE SINTETICA until the condition of the patient stabilizes.