Summary of Product Characteristics 1. NAME OF THE MEDICINAL PRODUCT NOREPINE 1mg/ml Concentrate for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Active substance: Norepinephrine base 1mg/ml in form of norepinephrine bitartrate 2mg/ml. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion (Sterile Concentrate). Aqueous solution for infusion, sterile, clear, colourless to yellowish, free of visible particles. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications - acute hypotension without fluid or blood depletion. - cardiovascular collapse. 4.2 Posology and method of administration To be used only by specialized medical personnel. Concentrate for solution for infusion to be diluted in a dextrose solution for injection. Strictly intravenous way. Control of the blood pressure necessary. Safety measure Site of injection: Norepinephrine is used by intravenous infusion only. Infusions of norepinephrine should be given into a large vein, particularly an antecubital vein because, in this case, the risk of necrosis of the overlying tissue due to a prolonged vasoconstriction is apparently weak. It is necessary to avoid the veins of the lower limbs. Blood pressure control: Every two minutes at the beginning of the infusion until the desired blood pressure is obtained. Then every five minutes when the desired blood pressure is obtained, if the administration has to be continued. The infusion flow rate must be controlled constantly, and the patient should never be left unattended during infusion. Extravasation risk: The infusion site should be checked frequently for free flow. Summary of Product Characteristics Care should be taken to avoid extravasation that should cause a necrosis of the tissues surrounding the vein used for the injection. Because of the vasoconstriction of the vein wall with increased permeability, there can be some leakage of norepinephrine in the tissues surrounding the infused vein causing a blanching of the tissues which is not due to an obvious extravasation. Hence if blanching occurs, consideration should be given to changing the infusion site to allow the effects of local vasoconstriction to subside. Treatment of the ischemia due to extravasation: During an extravascular leak of the product or of an injection beside the vein, a tissue destruction can appear resulting from the vasoconstrictive action of the drug on the blood vessels. The injection zone must be then irrigated as quickly as possible with 10 to 15ml of physiological salt solution containing 5 to 10 mg of phentolamine mesilate. For this purpose, it is necessary to use a syringe provided with a fine needle and to inject locally. The products administrated by injection must always be visually inspected and cannot be used if the presence of particles or a change of colouring is noted. Restoration of blood pressure In acute hypotensive states: Blood volume depletion should always be corrected as fully as possible before any vasopressor is administered. Norepinephrine can be administered before and during the blood volume replacement. Dilution: NOREPINE is a concentrated solution. Add 1 ampoule to 1000 ml of a 5 % dextrose solution or a mix (50/50 V/V) of dextrose 5% and sodium chloride 0,9%. With patients following a diet without salt, only a dextrose 5% solution will be used. Don’t mix the product with plasma or whole blood, if indicated to increase blood volume, it should be administered separately (for example, by use of a Y-tube or individual containers if given simultaneously). Usual dosage: Add a 4 ml ampoule (4 mg of norepinephrine base) to 1000 ml of a 5 % dextrose solution. Each ml of this dilution contains 4 microgram of norepinephrine base. Administrate this solution by intravenous infusion. Insert an intravenous catheter through a needle well advanced into the centrally vein and fix it with adhesive tape. A drip chamber or any other suitable measuring apparatus is essential to permit an accurate estimation of the flow rate. After observing the response of the initial dose of 2 to 3 ml of diluted solution ( 8 to 12 microgram of norepinephrine base) per minute (or 0,11 to 0,17 microgram/kg/min), adjust the flow rate to establish and maintain a normal blood pressure (usually 80 mm Hg to 100 mm Hg systolic) sufficient to maintain the circulation in vital organs. In previously hypertensive patients, it is recommended that the blood pressure should be raised no higher than 40 mm Hg below the pre-existing systolic pressure. Summary of Product Characteristics The average flow from 0.5 to 1 ml of diluted solution per minute (or 0,03 to 0,06 microgram/kg/min) permits generally to obtain satisfying blood pressure values. High Dosage: Above mentioned posology is not however absolute and is dependent of the state of the heart and the blood vessels of the patient. The sensitivity to the product differs considerably from one person to another. The administration of amounts going to 17 ampoules of 4ml per 24 h (corresponding to 0,67 microgram/kg/min) may be necessary if the patient remains hypotensive, but occult blood volume depletion should always be suspected and corrected if necessary. 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 volumes of fluid (dextrose) are needed to a flow rate that would involve an excessive dose of the pressor agent per unit of time, a solution more dilute than 4 microgram/ml should be used. On the other hand, when large volumes of fluid are clinically undesirable, a concentration greater than 4 microgram/ml may be necessary. Table of dilutions : The following table may be used as reference to calculate the dilutions and the number of the ampoules to obtain the requested concentration of Norepinephrine. Content in Norepinephrine Nb. of ampoules to Volume of dilution base to be obtained be used solution to be used 4 microgram/ml 1 1 litre 8 microgram/ml 2 1 litre 12 microgram/ml 3 1 litre 16 microgram/ml 4 1 litre 20 microgram/ml 5 1 litre Duration of Therapy: The duration of the treatment depends on each clinical case and can vary from a few hours up to six days. The infusion should be continued until blood pressure and an adequate tissues infusion are maintained without therapy. Norepinephrine infusions must be gradually reduced to avoid any abrupt withdrawal. Adjunctive treatment in cardiac arrest Norepinephrine infusions are usually administered intravenously during cardiac resuscitation to restore and maintain an adequate blood pressure after effective heartbeat and ventilation have been established by other means. The powerful ß1-adrenergic stimulating action of norepinephrine is also considered to increase the strength and effectiveness of systolic contractions when they occur. Usual dosage: To maintain systemic blood pressure during the treatment of cardiac arrest, norepinephrine is used in the same manner as described under “Restoration of blood pressure in acute hypotensive states”. Summary of Product Characteristics Information on the special populations Neonates The particular effects of norepinephrine in neonates are not well documented. Pediatric population Similar care must be exercised in giving norepinephrine to children as in adults. An initial dose of 0,05 microgram/kg/min of norepinephrine base may be infused with blood pressure monitoring and adjusted up to 0,5 microgram/kg/min norepinephrine base. The elderly The elderly are particularly susceptible to the effects of sympathomimetic agents and norepinephrine must be used cautiously. Hepatic and Renal Impairment The pharmacokinetics of norepinephrine are not significantly affected by renal or hepatic disease. As the bloodflow in organs like liver and kidneys could drop, caution should be exercised when using sympathicomimetics in patients with hepatic and renal impairment. 4.3 Contraindications NOREPINE is contra-indicated in the following cases: - Hypersensitivity to norepinephrine or to any of the excipients listed in section 6.1. NOREPINE contains sodium metabisulphite as excipient. May rarely cause severe hypersensitivity reactions and bronchospasm. - Hypertension: hypertensive patients may be more sensitive to the pressor effects of norepinephrine. - Hyperthyroidism: such patients are hypersensitive to the effects of norepinephrine and toxicity may occur in low doses. - Prinzmetal’s Angina: in such patients, coronary blood flow may be reduced to such an extent and duration as to cause myocardial infarction. - Hypotension due to blood volume deficit. - Hypercapnia, hypoxia and occlusive vascular disease. - During a chloroform, cyclopropane or halothane anaesthesia (see section 4.5). 4.4 Special warnings and precautions for use - Cardiovascular system: because of its alpha-agonist properties, when infusing norepinephrine, the blood pressure and rate of flow should be checked frequently from the time administration until the desired blood pressure is obtained to avoid hypertension. Norepinephrine should be used only in conjunction with appropriate blood volume replacement to avoid blood volume deficits. These could induce hypotension at the end of the treatment and cause vasoconstriction or vascular obstruction (see section 4.8). - Blood: in case of lack of oxygen or excessive concentration of blood carbonic gas, the use of NOREPINE can cause cardiac rhythm disorders (acceleration of the pulse or uncoordinated and ineffective contractions