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 of the heart) (see section 4.8.). - Extravasation : Norepinephrine is a severe tissue irritant and only very dilute solutions should be used. It should be infused centrally or into a large vein if possible, and care should be taken to avoid extravasation (see section 4.8). - NOREPINE contains sodium metabisulphite as excipient: may rarely cause severe hypersensitivity reactions and bronchospasm (see section 4.3). - NOREPINE contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially sodium free. Summary of Product Characteristics

- Metabolic troubles: hyperthyroidism (such patients are hypersensitive to the effects of norepinephrine and toxicity may occur in low doses), diabetes mellitus (decrease of the endocrine secretions). - Eyes: narrow angle glaucoma : patients with narrow angle glaucoma may have this symptom increased when sympathicomimetics such as norepinephrine are used (see section 4.8.). - Urogenital system: prostate hypertrophy : patients with prostatic hypertrophy may develop urinary retention (see section 4.8.). - Catecholamines, including Norepine, could play a role in the development of Tako-Tsubo cardiomyopathy following severe and acute stress (see section 4.8.). - It was observed that insulin sensitivity can be decreased by Norepine administration in lean adults without a history of diabetes mellitus or hypertension. This is possibly not due to altered insulin secretion. This suggests that insulin infusion rates will need to increase during times of hemodynamic support and decrease as these therapies are weaned and discontinued (see section 4.8.).

4.5 Interaction with other medicinal products and other forms of interaction NOREPINE is contra-indicated during a chloroform, cyclopropane or halothane anaesthesia because norepinephrine can increase excitability of the cardiac muscle and can cause rapid and irregularly contractions of the heart chamber (see section 4.3). Arrhythmias should be treated by administration of a B-adrenergic blocking drug such as propranolol.

Norepinephrine must be used with extreme caution in patients receiving the following drugs: - atropine sulfate because the reflex bradycardia caused by norepinephrine is blocked; - tricyclic antidepressants (ex. imipramine); - antihistamines (diphenhydramine, tripelennamine, dexchlorpheniramine); - certain alkaloids of ergotamine type, guanethidine, or methyldopa, because the vasopressor effects of the product can be potentiated and result in a severe and persistent hypertension; - MAOI (monoamine oxidase inhibitors), because severe and prolonged hypertension may result; - high amounts of digitalis or quinidine can cause arrhythmias; - furosemide or other diuretics, because they may decrease arterial responsiveness to norepinephrine. - entacapone : an increased risk of tachycardia, hypertension, and arrhythmias exists when administration of norepinephrine in patients receiving entacapone. - milnacipran : concomitant use of milnacipran and norepinephrine is associated with paroxysmal hypertension and possible arrhythmia due to the inhibition of norepinephrine reuptake by milnacipran.

Norepinephrine is incompatible with the following products: alkaline solutions or oxydative substances, barbiturates, chlorpheniramine, chlorothiazide, nitrofurantoine, novobiocine, phenytoine, sodium bicarbonate, sodium iodide, streptomycin, whole blood or plasma, cefamandole, cefoxitin, moxalactam.

The vasopressor effect (resulting from α-adrenergic action on the vessels), can be reduced by the concomitant administration of an α-blocking agent (phentolamine mesilate). Whereas the administration of a β--blocking agent (propranolol) can result in a reduction of the stimulating effect of the product on the heart (coming from a β1--adrenergic action) and result in an increase of the hypertensor effect following the reduction of arteriolar dilatation (coming from a ß2-adrenergic action) (see section 4.8). Summary of Product Characteristics

4.6 Fertility, pregnancy and lactation

Pregnancy Animal reproduction studies have not been conducted with norepinephrine and the effect is unknown. The drug should be used during pregnancy only when clearly needed. Norepinephrine can decrease the blood circulation in the placenta and cause a slowing of the fetus heart rhythm. It can also increase the contraction rate of the gravid uterus and involve an asphyxia of the fetus in late pregnancy. For this reason, it is advisable to use norepinephrine only in case of emergency for reanimation of the patient, if the discounted clinical advantages exceed the potential risks for the fetus.

Breastfeeding It is not known whether norepinephrine is distributed into human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with norepinephrine.

Fertility It is not known whether norepinephrine can affect reproduction capacity.

4.7 Effects on ability to drive and use machines NOREPINE doesn’t influence driving vehicles and using machines.

4.8 Undesirable effects

The undesirable effects described in literature are presented hereunder and classified by organ system and by frequency. Frequencies are defined as following : very common (≥ 1/10), common : (≥ 1/100 to <1/10), uncommon: (≥ 1/1.000 to < 1/100), rare (≥ 1/10.000 to < 1/1.000); very rare (< 1/10 000) ; not known (cannot be estimated from the available data).

As for sympathomimetics norepinephrine is an extremely potent peripheral vasoconstrictor and its adverse effects include hypertension (possibly associated with reflex bradycardia), headache, and peripheral ischaemia, which may be severe enough to result in gangrene of the extremities. Extravasation may lead to severe phlebitis and sloughing (see section 4.4.).

Table : known undesirable effects Organ system Undesirable effects Frequency Blood and lymphatic system Platelet aggregation resulting in thrombosis. not known disorders Contracting of the blood vessels which can uncommon result in coldness and paleness on the members and the face. Metabolism and nutrition Altered glucose metabolism (decreased not known disorders insulin sensitivity) (see section 4.4.) Nervous system disorders Anxiety, insomnia, confusion, cephalgia, uncommon headaches, psychotic state, weakness, tremor, lower vigilance, anorexia, nauseas, vomiting. Fear, restlessness and irritability. not known Eye disorders Acute glaucoma in persons anatomically very common Summary of Product Characteristics

predisposed with the closing of the iridocorn angle (see section 4.4.) Acute glaucoma (see section 4.4.) uncommon Cardiac disorders Tachycardia, bradycardia (probably as a common reflex result of blood pressure rising), arrhythmias, palpitations, increase in the contractility of the cardiac muscle resulting from the β-adrenergic effect on the heart (inotrope + and chronotrope+), acute cardiac insufficiency.

Cardiac arrest, sudden cardiac death, not known Tako-Tsubo cardiomyopathy (see section 4.4.) Vascular disorders Arterial hypertension and tissue hypoxia: very common Ischemic injury due to potent vasoconstrictor action (see section 4.4.). Respiratory, thoracic and Respiratory insufficiency or difficulty, uncommon mediastinal disorders dyspnea Renal and urinary disorders Urinary retention, decreased creatinine not known clearance. General disorders and Possibility of irritation and necrosis at the uncommon administration site conditions injection site.

The continuous administration of norepinephrine to maintain blood pressure, in absence of blood volume replacement may cause the following symptoms: - severe peripheral and visceral vasoconstriction - decrease in renal blood output - decrease in urine production - insufficient level of oxygen in tissues - increase in lactic acid level in blood.

In case of overdose or conventional doses in hypersensitive patients, the following effects may appear more frequently : hypertension, photophobia, retrosternal pain, pallor, intense sweating and vomiting.

The potentially life-threatening effects of norepinephrine stem from its dose-related hypertensive action. Acute hypertension with cerebral hemorrhage and pulmonary oedema may occur.

Extravasation of norepinephrine during an intravenous infusion leads to sloughing and necrosis around the infusion site. Gangrene of the extremities may follow prolonged infusions. Impaired circulation at infusion sites, with or without extravasation, may be relieved by hot packs and infiltration of the area with phentolamine (5 mg diluted to 10 ml with normal saline solution) (see section 4.4).

Norepinephrine has been shown to increase circulating levels of glycerol, acetoacetate, β- hydroxybutyrate and glucose. Lactate, pyruvate and alanine levels are decreased by norepinephrine.

Summary of Product Characteristics

The vasopressor effect (resulting from hypertension) can be reduced by the concomitant administration of an α-blocking (phentolamine mesilate). Whereas the administration of a β- blocking (propranolol) can result in a reduction of the stimulating effect of the product on the heart (coming from a cardiac arrhythmia) and result in an increase of the hypertensor effect following the reduction of arteriolar dilatation to the intervention of the β-receptors (see section 4.5).

Prolonged administration of any potent vasopressor may result in plasma volume depletion which should be continuously corrected by appropriate water and electrolyte replacement therapy. If plasma volumes are not corrected, hypotension may recur when the norepinephrine infusion is discontinued, or blood pressure may be maintained with the risk of severe peripheral and visceral vasoconstriction with diminution in blood flow (see section 4.4).

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 Federal Agency for Medicines and Health Products Vigilance Division EUROSTATION building, block 2 place Victor Horta, 40/ 40 B-1060 Brussels Site internet: www.afmps.be e-mail: [email protected]

4.9 Overdose

Symptoms Overdosage with norepinephrine may result in headache, severe hypertension, paleness, abnormally slow pulse, important increase of peripheral resistance and decreased cardiac output.

Treatment Discontinue immediately the administration until the condition of the patient stabilizes. Antidote: intravenous administration of an alpha-blocker such as phentolamine mesilate (5 to 10mg). This dose can be repeated if necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Adrenergic agent. ATC Code: C01CA03

Norepinephrine, is an endogenous catecholamine synthesized in the adrenal medulla and is the biochemical precursor of epinephrine. Norepinephrine is the neurotransmitter of most sympathetic postganglionic fibers of the central nervous system. Norepinephrine is a potent vasoconstrictor and inotrope. The naturally occurring form of Norepinephrine as well as the Summary of Product Characteristics

commercial formulation is available only as the levorotatory isomer, which is several times more potent than the dextrorotatory isomer, thus allowing the most potent form of the medication to be administered.

Norepinephrine acts on β1-receptors and predominantly on α-adrenergic receptors to produce constriction of resistance and capacitance vessels, thereby increasing systemic blood pressure and coronary artery blood flow. In relatively lower doses, the cardiac-stimulant effect of norepinephrine is predominant; with larger doses, the vasoconstrictor effect predominates.

Norepinephrine has direct agonist effects on effector cells that contain α- and β-receptors. As with other catecholamines, the intracellular action of norepinephrine is mediated via cyclic adenosine monophosphate (cAMP), the production of which is augmented by β stimulation and attenuated by α stimulation.

The primary pharmacodynamic effects of norepinephrine are cardiac stimulation, particularly at lower doses, and vasoconstriction, which tends to predominate with moderate to higher doses of the drug. Metabolic effects observed with adrenaline, such as glycogenolysis, inhibition of insulin release, and lipolysis, also occur with norepinephrine but are much less pronounced.

The haemodynamic consequences of norepinephrine's cardiovascular stimulation include increases in systolic, diastolic, and pulse pressures. Cardiac output is generally unaffected, although it can be decreased, and total peripheral resistance is also elevated. The elevation in resistance and pressure result in reflex vagal activity, which slows the heart rate and increases stroke volume. The elevation in vascular tone or resistance reduces blood flow to the major abdominal organs as well as to skeletal muscle. As with epinephrine, however, coronary blood flow is substantially increased secondary to the indirect effects of α stimulation. Therefore, unlike adrenaline, noradrenaline does not significantly increase myocardial oxygen consumption, except in patients with variant angina who are hyperresponsive to α stimulation.

Because norepinephrine is a sympathomimetic drug with agonist actions at both the α- and β- receptors, caution is warranted in patients receiving norepinephrine concomitantly with other sympathomimetics as additive pharmacodynamic effects are possible, some of which may be undesirable. This may result in an increased pressor reponse and an increased frequency of dysrhythmias during norepinephrine infusion.

5.2 Pharmacokinetic properties

Norepinephrine is rapidly and extensively metabolized in the gut and the liver and consequently is ineffective by oral administration due to a high first-pass effect. It is poorly absorbed from subcutaneous injection sites due to local vasoconstriction. As a result, it is recommended that norepinephrine be administered only via the intravenous route.

By intravenous administration of norepinephrine, the onset of activity is rapid, with a short duration of action of only 1 to 2 minutes following discontinuation of the infusion. The short plasma half-life of norepinephrine (2 to 2.5 min) is due to the fact that the drug is rapidly inactivated by enzymes in the liver and the kidney and by uptake and degradation in neuronal and non-neuronal tissue.

The metabolites of norepinephrine are excreted in urine primarily as sulphate and glucuronide Summary of Product Characteristics

conjugates. Up to 16% of an intravenous dose of norepinephrine is excreted unchanged in urine. The metabolic pathways of norepinephrine vary with the route of administration, and in particular there is a greater proportion of deaminated metabolites when norepinephrine is released from sympathetic nerve endings than when it is infused into the bloodstream.

At steady state, plasma norepinephrine levels are a consequence of the rate at which norepinephrine (exogenous and endogenous) enters plasma and the norepinephrine clearance from plasma. One can measure norepinephrine clearance by assay of plasma norepinephrine during a norepinephrine infusion or by assay of plasma 3H-norepinephrine concentrations during an infusion of a tracer dose of 3H-norepinephrine. The 3H-norepinephrine infusion technique to measure norepinephrine clearance has several advantages as a tracer dose of 3H- norepinephrine does not alter haemodynamics. Consequently, numerous pharmacokinetic studies have been carried out by using the 3H-norepinephrine infusion technique to determine norepinephrine plasma clearance and distribution volume. These studies showed that norepinephrine is rapidly cleared from plasma at 20 to 100 ml min-1 kg-1. This high norepinephrine plasma clearance together with a small distribution volume, 0.09 to 0.40 L kg- 1, results in a very short plasma half-life which ranges from 0.6 to 2.9 min. A linear relationship between norepinephrine dosing and norepinephrine plasma concentrations was shown in healthy volunteers and in critically ill head-injured patients. The pharmacokinetics of norepinephrine are not significantly affected by renal or hepatic disease.

Norepinephrine is only moderately (approximately 50%) bound to plasma proteins. It has a small volume of distribution of 0.09 to 0.40 L kg-1. Norepinephrine crosses the placenta but not the blood-brain barrier.

Basal levels of norepinephrine are 250 to 500 ng/ml. Hemodynamic effects are seen in adults at minimum concentrations of 1500 to 2000 ng/L. The usual initial rate of infusion of norepinephrine is 8 – 12 microgram/min. The rate is adjusted with close monitoring of blood pressure and the electrocardiogram to establish and maintain the required blood pressure. The usual maintenance rate of infusion of norepinephrine is 2 – 4 microgram/min.

5.3 Preclinical safety data No data is available.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients Sodium chloride Sodium metabisulphite Tartaric acid Water for injection.

6.2 Incompatibilities Norepinephrine is incompatible with the following products: alkaline solutions or oxydative substances, barbiturates, chlorpheniramine, chlorothiazide, nitrofurantoine, novobiocine, phenytoine, sodium bicarbonate, sodium iodide, streptomycin. NOREPINE cannot be mixed with plasma or whole blood but has to be administered separately.

Summary of Product Characteristics

6.3 Shelf life 3 years.

The diluted solutions of NOREPINE in form of infusion, prepared following the dilution way described at section 4.2. are stable during 24 hours in dextrose 5% solutions with or without sodium chloride 0,9% (mixture 50/50 V/V) at ambient temperature (15-25°C).

6.4 Special precautions for storage The NOREPINE ampoules have to be stored in the refrigerator at a temperature between 2 and 8°C protected from light until the expiry date mentioned on the box.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container Type I colourless glass ampoule of 5 ml containing 4 ml of solution. Eventual packaging in plastic blisters containing a single ampoule. Box contains 5, 10, 20, 50 or 100 ampoules.

6.6 Special precautions for disposal and other handling For product’s use method, see section 4.2. No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER LABORATOIRES STEROP Avenue de Scheut 46-50 - 1070 Brussels – Belgium

8. MARKETING AUTHORISATION NUMBER BE357244

9. DATE OF FIRST AUTHORISATION 08/01/2010

10. DATE OF REVISION OF THE TEXT 04/2014 Date of approbation :