Norepinephrine-novopharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOREPINEPHRINE-NOVOFARM (NOREPINEPHRINE-NOVOFARM)

Composition:

Active substance: norepinephrine (noradrenaline) tartrate;

1 ml of concentrate contains norepinephrine (noradrenaline) tartrate (as monohydrate) — 2.0 mg, equivalent to 1.0 mg of norepinephrine (noradrenaline) base;

Excipients: sodium chloride, sodium metabisulfite, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear liquid, colorless to slightly yellowish.

Pharmacotherapeutic group. Drugs affecting the cardiovascular system. Non-glycoside cardiotonic agents. Adrenergic and dopaminergic agents.

ATC code C01CA03.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Norepinephrine is a peripheral vasoconstrictor (alpha-adrenergic effect) and a cardiac inotrope stimulator and coronary artery dilator (beta-adrenergic effect).

The main pharmacodynamic effects of norepinephrine are vasoconstriction and cardiac stimulation. Cardiac output is usually unchanged, although it may be reduced, while total peripheral resistance increases. Increased resistance and pressure lead to reflex vagal activity, which reduces heart rate and increases stroke volume. Increased vascular tone reduces blood flow to major abdominal organs as well as to skeletal muscles. Coronary blood flow increases significantly due to indirect effects of alpha-stimulation. After intravenous administration, the pressor response occurs rapidly and reaches equilibrium within 5 minutes. The pharmacological action of norepinephrine is terminated primarily by uptake and metabolism in sympathetic nerve endings. Vasopressor effects cease within 1–2 minutes after discontinuation of infusion.

Pharmacokinetics

Absorption

Norepinephrine is rapidly inactivated in the gastrointestinal tract following oral administration.

After initiation of intravenous infusion, steady-state plasma concentration is achieved within 5 minutes.

Distribution

Plasma protein binding of norepinephrine is approximately 25%. Norepinephrine binds primarily to plasma albumin and to a lesser extent to prealbumin and alpha-1-acid glycoprotein. The volume of distribution is 8.8 L. Norepinephrine is predominantly localized in sympathetic nervous tissue. It crosses the placenta but does not cross the blood-brain barrier.

Metabolism

The mean half-life of norepinephrine is approximately 2.4 minutes. Mean metabolic clearance is 3.1 L/min.

Norepinephrine is metabolized in the liver and other tissues through combined reactions involving the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The main metabolites are normetanephrine and 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid), both inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylglycol, and 3,4-dihydroxyphenylglycol.

Excretion

Norepinephrine metabolites are excreted in urine primarily as sulfate conjugates and, to a lesser extent, glucuronide conjugates. Only small amounts of norepinephrine are excreted unchanged.

Clinical Characteristics

Indications. The medicinal product is indicated in adults for emergency restoration of arterial pressure in cases of acute hypotension.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Arterial hypotension caused by reduced circulating blood volume (hypovolemia).

Concomitant use with anesthetics containing cyclopropane and halothane. For interactions, see section "Interaction with other medicinal products and other forms of interactions". The use of pressor amines during anesthesia with cyclopropane or halothane may cause serious cardiac arrhythmias. Due to the increased risk of ventricular fibrillation, norepinephrine should be used with caution in patients receiving these or any other medicinal products that increase cardiac sensitivity, or in patients experiencing severe hypoxia or hypercapnia.

Avoid administration into veins of the lower extremities in elderly patients and in patients with occlusive vascular diseases due to possible vasoconstriction (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interactions

MAO Inhibitors

Concomitant use of norepinephrine with monoamine oxidase inhibitors (MAOIs) or other drugs that inhibit MAO (e.g., linezolid) may cause severe, prolonged hypertension.

Norepinephrine should be administered with extreme caution to patients receiving MAO inhibitors or within 14 days after discontinuation of such therapy. If administration of norepinephrine cannot be avoided in patients who have recently received MAO inhibitors and in whom MAO activity has not yet sufficiently recovered, careful monitoring for hypertension is required.

Tricyclic Antidepressants

Concomitant use of norepinephrine with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) may cause severe, prolonged hypertension. If administration of norepinephrine cannot be avoided, patients should be monitored for signs of hypertension.

Antidiabetic Agents

Norepinephrine may reduce sensitivity to insulin and increase blood glucose levels. Blood glucose levels should be monitored, and adjustment of antidiabetic drug dosage should be considered.

Halogenated Anesthetics

Concomitant use with halogenated anesthetics (e.g., cyclopropane, halothane, chloroform, desflurane, enflurane, isoflurane, and sevoflurane) may cause serious cardiac arrhythmias. Cardiac rhythm should be monitored in patients receiving halogenated anesthetics concurrently.

Due to the potential for increased risk of ventricular fibrillation, norepinephrine should be used with caution in patients receiving cardiac sensitizing agents or in those with severe hypoxia or hypercarbia.

The effects of norepinephrine may be potentiated by guanethidine, reserpine, methyldopa, or tricyclic antidepressants.

Concomitant administration of propofol and norepinephrine may lead to propofol infusion syndrome (PRIS).

Caution is required when using norepinephrine with alpha- and beta-blockers, as this may result in severe hypertension.

Norepinephrine should be used cautiously with drugs such as thyroid hormones, cardiac glycosides, and antiarrhythmic agents due to the risk of enhanced cardiac effects.

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

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Special precautions for use

Warnings

The medicinal product must not be administered undiluted (see section "Dosage and administration").

Norepinephrine should only be administered by healthcare professionals familiar with its specific use.

Norepinephrine should not be administered to patients suffering from hypotension due to blood volume deficiency. Norepinephrine should only be used in conjunction with appropriate circulatory blood volume replacement.

During infusion of norepinephrine, arterial pressure and infusion rate must be monitored frequently to avoid arterial hypertension.

Parenterally administered medicinal products should always be visually inspected; they must not be used if particulate matter is observed or if the solution has changed in color.

Precautions

Patients receiving norepinephrine must be under close observation so that early signs of limb ischemia caused by vasoconstrictors can be detected and appropriate measures taken (e.g., limb elevation, splinting, warming the affected limb with a special device, use of vasodilating agents) to prevent progression and minimize the risk of limb necrosis.

Hypovolemia should be addressed prior to initiating norepinephrine therapy. If a patient does not respond to treatment, occult hypovolemia should be suspected. Administration of norepinephrine to patients with hypotension due to hypovolemia may result in severe peripheral and visceral vasoconstriction, reduced renal perfusion, decreased urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow, despite a "normal" arterial pressure. Hypovolemia must be corrected before initiating norepinephrine therapy.

Particular caution is required in patients with thrombosis of coronary, mesenteric, or peripheral vessels, as norepinephrine may exacerbate ischemia and extend the infarct area, except when, in the physician’s judgment, administration of norepinephrine is necessary to save life. Similar caution should be exercised in patients with hypotension following myocardial infarction, patients with angina pectoris (especially Prinzmetal's variant angina), diabetes, hypertension, or hyperthyroidism.

Gangrene of the extremities has been reported in patients with occlusive or thrombotic vascular disease and in patients receiving prolonged or high-dose norepinephrine infusions; therefore, skin changes in the extremities should be monitored in susceptible patients. Administration into leg veins should be avoided in elderly patients or in patients with occlusive vascular disease of the legs.

Extravasation risk

Extravasation of the medicinal product (leakage from the vessel into surrounding tissues) may cause necrosis and sloughing of tissue around the infusion vein. To reduce the risk of extravasation, norepinephrine should be administered into a large vein, and the infusion site should be frequently checked for free flow and absence of signs of extravasation.

Emergency management of extravasation

To prevent sloughing and necrosis at sites of extravasation, the ischemic area should be infiltrated as soon as possible using a syringe with a fine subcutaneous needle, adding 5–10 mg of phentolamine mesilate to 10–15 mL of 0.9% sodium chloride solution. Sympathetic blockade by phentolamine causes immediate and marked local hyperemic changes if infiltration is performed within 12 hours. Phentolamine should be administered as quickly as possible after extravasation is detected and infusion discontinued.

Hypotension following abrupt discontinuation of infusion

Infusion of norepinephrine should be tapered gradually by reducing the flow rate while simultaneously increasing blood volume with intravenous fluids, as abrupt cessation may lead to catastrophic drop in arterial pressure.

Cardiac arrhythmias

Norepinephrine increases intracellular calcium concentrations and may cause arrhythmias, especially in patients with signs of marked hypoxia or hypercapnia. Therefore, continuous cardiac monitoring should be performed in patients with arrhythmias.

Allergic reactions

The medicinal product contains sodium metabisulfite, which may cause hypersensitivity reactions, including anaphylactic symptoms and asthma attacks of varying severity, particularly in patients with bronchial asthma. The overall prevalence of sulfite sensitivity in the general population is unknown.

This medicinal product contains sodium, which should be taken into account if the patient is on a sodium-restricted diet.

1 mL of concentrate for preparation of infusion solution contains 3.3 mg of sodium, equivalent to 0.14 mmol of sodium.

1 vial (4 mL of medicinal product) contains 13.2 mg of sodium, equivalent to 0.57 mmol of sodium.

Elderly patients

Elderly individuals may be particularly sensitive to the effects of norepinephrine due to higher prevalence of impaired liver, kidney, or heart function, concomitant diseases, or use of other medications. Administration of norepinephrine into leg veins should be avoided in elderly patients.

Children

The safety and efficacy of norepinephrine in children under 18 years of age have not been established.

Use during pregnancy or breastfeeding

Pregnancy

Norepinephrine may negatively affect placental blood flow and cause fetal bradycardia. The medicinal product may also affect uterine contractions in pregnant women and lead to fetal asphyxia in late pregnancy. Therefore, careful consideration should be given to whether the expected benefit to the mother outweighs the potential risk to the fetus.

Hypotension associated with septic shock, myocardial infarction, and stroke are medical emergencies during pregnancy that may be fatal if untreated. Delaying treatment of pregnant women with hypotension due to septic shock, myocardial infarction, or stroke may increase the risk of morbidity and mortality for both mother and fetus. Therefore, life-sustaining therapy in pregnant women should not be withheld due to potential concerns about the effects of norepinephrine on the fetus.

Breastfeeding

Data on the use of norepinephrine during lactation are lacking.

Fertility

No studies have been conducted to assess the effect of norepinephrine on fertility.

Ability to affect reaction speed when driving or operating machinery

Data are lacking. Therefore, driving or operating machinery is not recommended.

Administration and Dosage

Administration method

The medicinal product is intended for intravenous use after dilution.

The diluted noradrenaline solution should be administered via a central venous catheter. The infusion rate should be controlled using a syringe pump, infusion pump, or drip counter.

Medicinal product dilution

Do not use the medicinal solution if it is pink or darker than slightly yellow, or if it contains a precipitate.

Add 2 mL of concentrate to 48 mL of 5% glucose solution (or sodium chloride 9 mg/mL (0.9%) with glucose 50 mg/mL (5%)) for administration via syringe infusion pump, or add 20 mL of concentrate to 480 mL of 5% glucose solution (or sodium chloride 9 mg/mL (0.9%) with glucose 50 mg/mL (5%)) for administration via infusion drip.

In both cases, the final concentration of the infusion solution is 80 mg/L of noradrenaline tartrate, equivalent to 40 mg/L of noradrenaline base.

It is not recommended to use only sodium chloride physiological saline for dilution. The use of glucose solution significantly reduces loss of medicinal product activity due to oxidation.

The medicinal product vial is intended for single use only. Any unused concentrate or diluted medicinal product should be disposed of according to current regulations.

Dosage

Adult patients

The initial infusion rate (intravenous administration) for a 70 kg body weight should be 10–20 mL/hour (0.16–0.33 mL/min), equivalent to 0.4–0.8 mg/hour of noradrenaline base (0.8–1.6 mg/hour of noradrenaline tartrate).

Depending on the clinical situation, treatment may be initiated at a lower initial infusion rate of 5 mL/hour (0.08 mL/min), equivalent to 0.2 mg/hour of noradrenaline base (0.4 mg/hour of noradrenaline tartrate).

Dose titration

Immediately after starting noradrenaline infusion, the dose should be titrated in increments of 0.05–0.1 mcg/kg/min of noradrenaline base according to the observed pressor effect. There is considerable individual variation in the dose required to achieve and maintain normal blood pressure in patients. The main goal is to establish a low-normal systolic blood pressure (100–120 mmHg) or to achieve an appropriate mean arterial pressure (greater than 65–80 mmHg—depending on the patient's condition).

Table 1

Dose titration of noradrenaline infusion solution

Noradrenaline infusion solution 40 mg/L (40 mcg/mL) of noradrenaline base
Patient body weight	Dosing (mcg/kg/min) of noradrenaline base	Dosing (mg/h) of noradrenaline base	Infusion rate (mL/h)
50 kg	0.05	0.15	3.75
	0.1	0.3	7.5
	0.25	0.75	18.75
	0.5	1.5	37.5
	1	3	75
60 kg	0.05	0.18	4.5
	0.1	0.36	9
	0.25	0.9	22.5
	0.5	1.8	45
	1	3.6	90
70 kg	0.05	0.21	5.25
	0.1	0.42	10.5
	0.25	1.05	26.25
	0.5	2.1	52.5
	1	4.2	105
80 kg	0.05	0.24	6
	0.1	0.48	12
	0.25	1.2	30
	0.5	2.4	60
	1	4.8	120
90 kg	0.05	0.27	6.75
	0.1	0.54	13.5
	0.25	1.35	33.75
	0.5	2.7	67.5
	1	5.4	135

Other dilutions different from 40 mg/L of noradrenaline base (or 80 mg/L of noradrenaline tartrate) may be used; however, the dosage calculation and infusion rate must be carefully checked before starting the infusion.

Treatment duration and monitoring

Noradrenaline treatment should be continued until adequate arterial pressure and tissue perfusion are maintained without therapy. Throughout the entire period of noradrenaline administration, careful patient observation and monitoring of arterial pressure are required.

Discontinuation of therapy

The drug administration should be gradually reduced, as abrupt discontinuation of noradrenaline may lead to the development of acute arterial hypotension.

Elderly patients

Elderly patients may be particularly sensitive to the effects of noradrenaline.

Patients with renal or hepatic impairment

There is no experience with noradrenaline treatment in patients with renal or hepatic impairment.

Children

The use of the medicinal product in children is not recommended. Data on the safety and efficacy of noradrenaline in children under 18 years of age are lacking.

Overdose

Overdose may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and reduced cardiac output. These signs may be accompanied by severe headache, intracerebral hemorrhage, photophobia, chest pain, pallor, fever, profuse sweating, pulmonary edema, and vomiting.

In case of overdose, treatment should be discontinued and appropriate corrective therapy should be initiated.

Adverse Reactions

Table 2 lists adverse reactions observed during the use of norepinephrine. The data were collected from spontaneous reports; therefore, the frequency of the listed adverse reactions is unknown (cannot be estimated from the available data).

Table 2

Adverse reactions of norepinephrine based on spontaneous reporting data

Psychiatric	Anxiety, insomnia, confusion, weakness, psychotic state
Nervous system disorders	Transient headache, tremor
Cardiac disorders	Tachycardia, bradycardia (possibly as a reflex response to increased blood pressure), arrhythmia, ECG changes, cardiogenic shock, stress-induced cardiomyopathy, palpitations, increased myocardial contractility due to beta-adrenergic cardiac effects (inotropic and chronotropic)
Vascular disorders	Hypertension, peripheral ischemia1, including limb gangrene, reduced plasma volume with prolonged use
Skin and subcutaneous tissue disorders	Pallor, skin sloughing, cyanosis, flushing or skin redness, rash, urticaria or pruritus
Respiratory, thoracic and mediastinal disorders	Dyspnea, labored breathing
General disorders and administration site conditions	Extravasation, injection site necrosis

1 Ischemia due to potent vasoconstrictive action and tissue hypoxia.

With prolonged use of vasopressors (vasoconstrictive agents) to maintain arterial pressure in the absence of restoration of circulating blood volume, the following symptoms may occur:

• severe constriction of peripheral and visceral blood vessels;
• reduced renal blood flow;
• decreased urine output;
• hypoxia (oxygen deficiency);
• increased serum lactate levels.

In case of hypersensitivity (allergic reaction) or overdose, the following symptoms may occur more frequently: arterial hypertension, photophobia, substernal pain, throat pain, pallor, excessive sweating, and vomiting.

The vasopressor effect (resulting from adrenergic action on blood vessels) may be reduced by concomitant administration of an alpha-blocker (phentolamine mesylate), whereas the use of a beta-blocker (propranolol) may lead to reduced stimulatory effect of the drug on the heart and to increased pressor effect (due to reduced arteriolar dilation), which occurs as a result of beta-1-adrenergic stimulation.

Prolonged use of any potent vasopressor may lead to a reduction in plasma volume, which must be continuously corrected with appropriate fluid and electrolyte replacement therapy. If plasma volume is not corrected, arterial hypotension may recur when norepinephrine infusion is discontinued, or arterial pressure may be maintained at the risk of severe constriction of peripheral and visceral blood vessels, resulting in reduced blood flow.

Hypertension may occur, which may be associated with bradycardia, headache, and peripheral ischemia, including limb gangrene.

Cardiac arrhythmias may occur when norepinephrine is used concomitantly with cardiac sensitizing agents, most commonly in patients with hypoxia or hypercarbia. Norepinephrine should be administered only with appropriate blood volume compensation. Prolonged infusion may lead to decreased blood plasma volume. During norepinephrine administration, arterial pressure and flow rate should be monitored frequently to avoid hypertension, which may be associated with bradycardia, headache, and peripheral ischemia, including gangrene. Extravasation may cause local tissue necrosis.

Particular caution is required in patients with hepatic insufficiency, severe renal dysfunction, ischemic heart disease, and increased intracranial pressure. Overdose or usual doses in hypersensitive individuals (e.g., patients with hyperthyroidism) may cause severe hypertension with severe headache, photophobia, stabbing chest pain, pallor, profuse sweating, and vomiting. Hypertension over time may lead to acute pulmonary edema, arrhythmias, or cardiac arrest.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Do not use after the expiry date.

Shelf life after opening the vial

After opening the vial, the diluted solution should be prepared immediately.

Shelf life after dilution

Chemical and physical stability of the medicinal product has been demonstrated when diluted to 40 mg/L of norepinephrine in 5% glucose solution or in sodium chloride 9 mg/mL (0.9%) solution with glucose 50 mg/mL (5%) and stored for 24 hours at room temperature (from 20 °C to 25 °C) in a light-protected environment or at 2–8 °C.

From a microbiological standpoint, the diluted medicinal product should be used immediately. If the solution is not used immediately, the responsibility for the duration and conditions of storage lies solely with the user.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility

This medicinal product must not be mixed with other medicinal products except those specified in the section "Administration and dosage".

It has been reported that infusion solutions containing norepinephrine tartrate are incompatible with the following substances: iron salts, alkalis and oxidizing agents, barbiturates, chlorpheniramine, chlorothiazide, nitrofurantoin, novobiocin, phenytoin, sodium bicarbonate, sodium iodide, streptomycin, sulfadiazine, sulfadiazoline.

Whole blood or plasma, if indicated for increasing blood volume, should be administered separately.

Prescription category. Prescription only.

Packaging. 4 mL in a vial; 5 vials in a blister pack; 2 blister packs in a carton.

Manufacturer. Limited liability company "Novofarm-Biosyntez".

Manufacturer's address and location of its business activity. Ukraine, 11700, Zhytomyr Oblast, Zviahel Raion, city of Zviahel, 38 Zhytomyrska Street.