Indicated for use as an emergency measure in the restoration of blood pressure in cases of acute hypotension.

Noradrenalin Sintetica 4mg/4ml will be used to you in hospital by a doctor or nurse. Noradrenaline Sintetica 4mg/4ml without disulphite is administered by pump-controlled infusion (Perfusor, infusion pump). The initial dose of Noradrenalin Sintetica 4 mg/4 ml will depend on your medical condition The solution for infusion is generally prepared from 4 ml of Noradrenaline Sintetica without disulphite (= 4 mg of noradrenaline base) diluted in 1 litre of 5% glucose, NaCl 0.9% and glucose saline solution.  Before any use, carefully check the accuracy of the dilution. The smallest effective dose of noradrenaline should be administered for the shortest possible necessary time. Your doctor will determine the correct dose for you. After the initial dose your doctor will assess your response and adjust the dose accordingly

Noradrenalin Sintetica without disulfite Noradrenalin Sintetica without disulfite should only be administered by healthcare professionals who are familiar with its use.

Warnings

-          Noradrenaline should be used only in conjunction with appropriate blood volume replacement.

-          When infusing noradrenaline, the blood pressure and rate of flow should be checked frequently to avoid hypertension.

-          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.

-          Extravasation risk:

The infusion site should be checked frequently for free flow. Care should be taken to avoid extravasation that would cause a necrosis of the tissues surrounding the vein used for injection. Because of the vasoconstriction of the vein wall with increased permeability, there might be some leakage of noradrenaline 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 an injection besides 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 15 ml of physiological salt solution containing 5 to 10 mg phentolamine mesilate. For this purpose, it is necessary to use a syringe provided with a fine needle and to inject locally.

Precautions for use

Caution and respect of the strict indication must be retained in case of:

-          Major left ventricular dysfunction associated with acute hypotension, a careful evaluation of patient´s blood pressure is needed. Supportive therapy should be initiated simultaneously with diagnostic evaluation. Noradrenaline should be reserved for patients with cardiogenic shock and refractory hypotension, in particular those without elevated systemic vascular resistance. It should be started at a dosage of 2 to 4 µg/min and titrated upwards and titrated as necessary. If systemic perfusion or systolic pressure cannot be maintained at > 90 mmHg with a dosage of 15 µg/min, it is unlikely that a further increase will be beneficial.

-          Particular caution should be observed in patients with coronary, mesenteric or peripheral vascular thrombosis because noradrenaline may increase the ischaemia and extend the area of infarction. Similar caution should be observed in patients with hypotension following myocardial infarction and in patients with Prinzmetal´s variant angina.

-          Occurrence of heart rhythm disorders during the treatment must lead to a reduction in the dosage.

-          Caution is advised in patients with hyperthyroidism or diabetes mellitus.

-          Elderly patients may be especially sensitive to the effects of noradrenaline.

Perfusion of noradrenaline must be performed with continuous monitoring of blood pressure and cardiac frequency.

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 the infusion 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.

The vasopressor effect (resulting from the adrenergic action in the vessels) can be reduced by the concomitant administration of an alpha-blocking agent whereas the administration of a beta-blocking agent may result in a reduction of the stimulating effect of the product on the heart and in an increase of the hypertensive effect (through reduction of arteriolar dilatation), resulting from beta-1-adrenergic stimulation.

In cases where it is necessary to administer noradrenaline at the same time as total blood or plasma, the latter must be administered in a separate drip.

Each ampoule containing 1 ml of concentrate for solution for infusion contains 0.14 mmol (or 3.3 mg) sodium.

Each ampoule containing 4 ml of concentrate for solution for infusion contains 0.57 mmol (or 13.2 mg) sodium.

Each ampoule containing 10 ml of concentrate for solution for infusion contains 1.44 mmol (or 33 mg) sodium.

This should be taken into consideration by patients on a controlled sodium diet (see section 2).

Inadvisable combinations

-          Volatile halogen anaesthetics: severe ventricular arrhythmia (increase in cardiac excitability.

-          Imipramine antidepressants: paroxysmal hypertension with the possibility of arrhythmia (inhibition of the entry of sympathomimetics into sympathetic fibers).

-          Serotoninergic-adrenergic antidepressants: paroxysmal hypertension with the possibility of arrhythmia (inhibition of the entry of sympathomimetics into sympathetic fibers).

Combinations requiring precautions for use

-          Non-selective MAO inhibitors: increase in the pressor action of the sympathomimetic which is usually moderate. Should only be used under close medical supervision.

-          Selective MAO-A inhibitors: by extrapolation from non-selective MAO inhibitors, risk of increase in the pressor action. Should only be used under close medical supervision.

-          Linezolid: by extrapolation from non-selective MAO inhibitors, risk of increase in the pressor action. Should only be used under close medical supervision.

Caution is required when using noradrenaline with beta-blockers as severe hypertension may result.

Caution is required when using noradrenaline with the following drugs as they may cause increased cardiac effects: thyroid hormones, cardiac glycosides, antiarrhythmic agents.

Ergot alkaloids or oxytocin may enhance the vasopressor and vasoconstrictive effects.

Pregnancy

Noradrenalin Sintetica without disulfiteNoradrenalin Sintetica without disulfite may impair placental perfusion and induce fetal bradycardia. It may also exert a contractile effect on the pregnant uterus and lead to fetal asphyxia in late pregnancy. These possible risks to the fetus should therefore be weighed against the potential benefit to the mother.

Breast-feeding

No information is available on the use of Noradrenalin Sintetica without disulfiteNoradrenalin Sintetica without disulfite in lactation.

None stated.

The frequency of the adverse reactions cannot be estimated from the available data.

The continuous administration of vasopressor to maintain blood pressure in absence of blood volume replacement may cause the following symptoms:

-          severe peripheral and visceral vasoconstriction

-          decrease in renal blood flow

-          decrease in urine production

-          hypoxia

-          increase in lactate serum levels.

In case of hypersensitivity or overdose, the following effects may appear more frequently: hypertension, photophobia, retrosternal pain, pharyngeal 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. Healthcare professionals are asked to report any suspected adverse reactions via the National Pharmacovigilance and Drug Safety Center (NPC).

-To Report any side effect(s):

• Saudi Arabia:

• Other GCC states:

Overdosage may result in severe hypertension, reflex bradycardia, marked increase in peripheral resistance and decreased cardiac output. These may be accompanied by violent headache, photophobia, retrosternal pain, pallor, intense sweating and vomiting. In the event of overdosage, treatment should be withdrawn and appropriate corrective treatment initiated

Pharmacotherapeutic group: Adrenergic and dopaminergic agents, ATC code: C01CA03

Mechanism of action

The vascular effects in the doses normally used clinically result from the simultaneous stimulation of alpha and beta adrenergic receptors in the heart and vascular system. Except in the heart, its action is predominantly on the alpha receptors.

Pharmacodynamic effects

This results in an increase in the force (and in the absence of vagal inhibition, in the rate) of myocardial contraction. Peripheral resistance increases, and diastolic and systolic pressures are raised.

Clinical efficacy and safety

The increase in blood pressure may cause a reflex decrease in heart rate. Vasoconstriction may result in decreased blood flow in kidneys, liver, skin and smooth muscles. Local vasoconstriction may cause haemostasis and/or necrosis.

The effect on blood pressure disappears 1-2 minutes after stopping the infusion.

Two stereoisomers of noradrenaline exist, the biologically active L-isomer is the one present in noradrenaline 1 mg/ml concentrate for solution for infusion.

Absorption:

-          Subcutaneous: poor

-          Oral: noradrenaline is rapidly inactivated in the gastrointestinal tract following oral administration

-          After intravenous administration noradrenaline has a plasmatic half-life of about 1 to 2 minutes.

Distribution:

-          Noradrenaline is rapidly cleared from plasma by a combination of cellular reuptake and metabolism. It does not readily cross the blood-brain barrier.

Biotransformation:

-          Methylation by catechol-o-methyltransferase

-          Deamination by monoamine oxydase (MAO)

-          Ultimate metabolites from both is 4-hydroxy-3-methoxymandelic acid

-          Intermediate metabolites include normetanephrine and 3,4-dihydroxymandelic acid.

Elimination:

Noradrenaline is mainly eliminated as glucuronide or sulphate conjugates of the metabolites in the urine.

Most of the adverse effects attributable to sympathomimetics result from excessive stimulation of the sympathetic nervous system via the different adrenergic receptors.

Noradrenaline may impair placental perfusion and induce fetal bradycardia. It may also exert a contractile effect on the uterus and lead to fetal asphyxia in late pregnancy.

Sodium chloride

Water for injections

Noradrenalin Sintetica without disulfiteNoradrenalin Sintetica without disulfite must not be mixed with other medicinal products except those mentioned in section 6.6.

Infusion solutions containing noradrenaline tartrate have been reported to be incompatible with the following substances: alkalis and oxidising agents, barbiturates, chlorpheniramine, chlorothiazide, nitrofurantoin, novobiocin, phenytoin, sodium bicarbonate, sodium iodide, streptomycin.

For compatibility with infusion bags see section 6.6.

Do not store above 30 °C. Do not refrigerate or freeze.

Store in original package in order to protect from light.

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

Noradrenalin Sintetica without disulfiteNoradrenalin Sintetica without disulfite 1 mg/1 ml

Type I one point cut clear colorless glass 2 ml ampoules one-point cut.

Box of 10 ampoules containing 1 ml of concentrate for solution for infusion.

Noradrenalin Sintetica without disulfiteNoradrenalin Sintetica without disulfite 4 mg/4 ml

Type I one point cut clear colorless glass 5 ml ampoules one point cut.

Box of 10 ampoules containing 4 ml of concentrate for solution for infusion.

Noradrenalin Sintetica without disulfite 10 mg/10 ml

Type I one point cut clear colorless glass 10 ml ampoules one-point cut.

Box of 10 ampoules containing 10 ml of concentrate for solution for infusion.

Not all pack sizes may be marketed.

Dilution instructions:

Dilute before use with glucose 5% solution or sodium chloride 9 mg/ml (0.9%) or sodium chloride 9 mg/ml with glucose 5 % solution.

The product is compatible with PVC infusion bags.

Any unused product or waste material should be disposed of in accordance with local requirements.