PATIENT INFORMATION LEAFLET

NORAGES 1 mg/ml injectable solution

L-norepinephrine base

Read this leaflet carefully before you start taking this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only, and you must not give it to others, even if they have the same symptoms as you, as it may harm them.
• If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are not listed in this leaflet.

Norages is a medication that belongs to the group of "adrenergic and dopaminergic agents", which acts by increasing blood pressure.

Norages is indicated for the treatment of acute hypotension (decreased blood pressure)

No use Norages:

• If you are allergic (hypersensitive) to L-norepinephrine bitartrate monohydrate or to any of the other components of this medication
• If during anesthesia, you will be administered other medications such as halothane or cyclopropane.
• If you have ulcers or gastrointestinal bleeding.

Be especially careful with Norages if:

• You are diabetic
• You have hyperthyroidism
• Your oxygenation state is insufficient
• You have any occlusive (obstructive) disease such as arteriosclerosis (hardening of the arteries), Buerger's disease (inflammation of a vein with formation of a thrombus), diabetes mellitus.
• You have had thrombosis.

Warnings and precautions

Consult your doctor or pharmacist before starting to use this medication.

Use of Norages with other medications

Inform your doctor or pharmacist that you are using, have used recently, or may have to use any other medication.

Certain medications may interact with Norages, requiring a change in the dose of Norages and/or the aforementioned medications and administering them with caution.

It is essential to inform your doctor if you are using or have used recently any of the following medications:

• Organic anesthetics
• Tricyclic antidepressants (used to treat depression) or maprotiline
• Digitalis glycosides (heart medications)
• Ergoloid mesylates or ergotamine (headache medications)
• Levodopa (Parkinson's disease medication)
• Cocaine
• Guanadrel and guanetidine (hypertension medications)
• Chlorpheniramine hydrochloride, tripelennamine hydrochloride (allergy medications) and desipramine (depression medication)
• Antihistamines (allergy medications).
• Amphetamines (central nervous system stimulant medication)
• Dihydroergotamine (headache medication) ergometrine, methylergometrine (medications for postpartum or abortion hemorrhage) or methysergide (headache medication)
• Doxapram (respiratory stimulant medication)
• Mazindol (obesity medication)
• Mecamilamine (smoking cessation medication) or methyldopa (hypertension medication)
• Methamphetamine (central nervous system stimulant medication)
• Rauwolfia alkaloids (hypertension medication)
• Other sympathomimetics (medications that increase blood pressure)
• Thyroid hormones (metabolic disorder treatment)
• Monamine oxidase inhibitors (MAOIs) (depression medications)
• Diuretics (medications for hypertension or increased urine elimination)
• Beta-adrenergic blockers (medications to reduce blood pressure)
• Desmopressin (medication for nocturnal incontinence), lisopressin or vasopressin (medications for hypotension and antidiuresis)
• Lithium (medication for mental disorders)

Pregnancy, lactation, and fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medication, as there may be risks for the unborn child.

The excretion of Norages in breast milk is unknown, so your doctor will assess the need for its administration.

Norages 1 mg/ml contains sodium.

This medication contains less than 23 mg (1 mmol) of sodium per 4 ml ampoule, making it essentially "sodium-free".

Follow exactly the administration instructions for Norages 1 mg/ml as indicated by your doctor. In case of doubt, consult your doctor again.

Norages 1 mg/ml is administered intravenously by a healthcare professional.

Adults

The initial dose is administered at a rate of 8 to 12 micrograms (base) per minute. For maintenance, the rate is adjusted to 2 to 4 micrograms (base) per minute.

In the case of septic shock, doses should be adjusted around 0.5 micrograms per kilogram and per minute (up to a maximum of 1.0 micrograms per kilogram and per minute).

Children

Intravenous infusion, 0.1 micrograms (base) per kilogram and per minute. Up to a maximum of 1 microgram (base) per kilogram and per minute.

If you use more Norages than you should:

You may experience a severe increase in blood pressure with intense headache, photophobia, acute chest pain, throat pain, pallor, intense sweating, and vomiting.

In case of overdose or accidental ingestion, consult the Toxicological Information Service. Phone: 91 – 5620420.

Like all medications, Norages can produce side effects, although not everyone will experience them

Vein leakage can cause destruction of the surrounding tissue

It can cause a decrease in heart rate

Prolonged use can decrease heart output

Prolonged administration of this type of substance can cause blood loss, which, if not corrected, can cause a relapse in blood pressure when treatment is suspended

It can cause severe narrowing of the body's veins and viscera (e.g., decreased blood flow to the kidney) with decreased blood flow and tissue perfusion, resulting in tissue hypoxia, increased blood acidity, and damage due to poor blood flow

Although rare, the following symptoms may occur during application and require medical attention:

Skin disorders: Pale skin along the infusion vein, scarring, blue discoloration, flushing or redness of the skin, skin rash, urticaria, or pruritus

Cardiovascular system disorders: Irregular heartbeats, decreased heart rate

Respiratory system disorders: Wheezing or difficulty breathing

General disorders: Severe dizziness or feeling of fainting

Less frequently, the following symptoms may occur and require medical attention only if they last or are bothersome:

Skin disorders: Pale skin

Cardiovascular system disorders: Palpitations

Nervous system disorders: Anxiety or restlessness, sleep problems, tremors, headache

General disorders: Dizziness, swelling in the neck

In sensitive individuals, for example, people with nervous system diseases or hyperthyroidism, it produces:

Nervous system disorders: Fear, anxiety, pulsating headache, and difficulty breathing

Cardiovascular system disorders: Pale skin, tachycardia, palpitations, slight elevation of blood pressure

If you experience side effects, consult your doctor or pharmacist, even if they are side effects that do not appear in this prospectus

Reporting side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use: www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medication

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Do not store at a temperature above 25°C. Store in the original packaging to protect from light.

Medications should not be disposed of through drains or in the trash. If in doubt, ask your pharmacist how to dispose of unused packaging and medication. By doing so, you will help protect the environment.

Composition of Norages

The active principle is noradrenaline (L-norepinephrine) base.

Each milliliter of solution contains 1 mg of noradrenaline (L-norepinephrine) base equivalent to 2 mg of noradrenaline bitartrate (L-norepinephrine) monohydrate.

Each ampoule of 4 ml contains 4 mg of noradrenaline (L-norepinephrine) base equivalent to 8 mg of noradrenaline bitartrate (L-norepinephrine) monohydrate.

The other components (excipients) are sodium chloride and water for injectable preparations.

Aspect of the product and content of the packaging

Norages 1 mg/ml is an injectable solution that is presented in containers containing 10 ampoules of 4 ml.

Holder of the marketing authorization and responsible for manufacturing

Altan Pharmaceuticals, S.A.

C/ Cólquide 6, Portal 2, 1st floor, office F

Edificio Prisma

28230 Las Rozas – Madrid, Spain

Responsible for manufacturing:

Laboratorio RENAUDIN

Z.A. Errobi

64250 Itxassou, France

This prospectus was approved in July 2019

The detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es

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This information is intended solely for doctors or healthcare professionals:

Dosage and administration

Norepinephrine should be administered intravenously:

Usual adult dosage

The initial dose is administered at a rate of 8 to 12 micrograms (0.008 to 0.012 mg) (base) per minute, adjusting the rate of administration to establish and maintain the desired blood pressure.

To maintain, the rate is adjusted from 2 to 4 micrograms (0.002 to 0.004 mg) (base) per minute, titrating the dosage according to the patient's response.

In the case of septic shock, the doses should be adjusted around 0.5 micrograms/kg/min (up to a maximum of 1.0 micrograms/kg/min) to achieve the desired mean blood pressure. It is recommended to administer it along with doses of 2 – 2.5 micrograms/kg/min of dopamine, which counteract vasoconstriction, ensuring good renal and splenic circulation.

- To prepare the solution for intravenous infusion of norepinephrine, add 4 mg of L-norepinephrine (base) to 1 liter of 5% glucose solution. The resulting solution will contain 4 micrograms (0.004 mg) of L-norepinephrine (base) per ml. It should be noted that 1 mg of L-norepinephrine bitartrate is equivalent to 0.5 mg of L-norepinephrine base.

Duration of treatment

The infusion should be continued until the desired blood pressure and tissue perfusion are maintained without treatment. The norepinephrine infusion should be gradually reduced, avoiding abrupt interruption. In some cases described of vascular collapse due to acute myocardial infarction, treatment was required for up to six days.

Usual pediatric dosage

Intravenous infusion, 0.1 micrograms (base) per kg per minute, adjusting the rate of administration gradually to achieve the desired blood pressure, up to 1 microgram (base) per kg per minute.

- When added to local anesthetics, these solutions contain a concentration of norepinephrine around 1: 200,000 (5 micrograms/ml).

Administration should be avoided:

- Norepinephrine should not be used as the sole therapy in hypotensive patients due to hypovolemia, except as an emergency measure to maintain coronary and cerebral perfusion until volume replacement therapy is completed.

- Administration should be avoided in the veins of the lower limbs of elderly patients and patients with occlusive diseases due to possible vasoconstriction.

- Accidental cases may occur where, if proper precautions are not taken, extravasation or even gangrene may occur. To avoid necrosis and scarring of the tissue in the area where extravasation has occurred, the area should be infiltrated immediately with 10 to 15 ml of sodium chloride solution containing 5 to 10 mg of fentolamine. A hypodermic needle and syringe should be used, and the solution should be infiltrated abundantly throughout the area. If the area is infiltrated within 12 hours, the sympathetic block with fentolamine produces immediate and perceptible local hyperemia.

- The lost blood volume should be replenished as completely as possible before administering any vasopressor.

Special precautions for use

- Before administration, norepinephrine injectable should be diluted with 5% glucose solution in distilled water or 5% glucose solution in sodium chloride solution. Sodium chloride solution alone should not be used.

- To prepare the solution for intravenous infusion of norepinephrine, add 4 mg of L-norepinephrine (base) to 1 liter of 5% glucose solution. The resulting solution will contain 4 micrograms (0.004 mg) of L-norepinephrine (base) per ml. It should be noted that 1 mg of L-norepinephrine bitartrate is equivalent to 0.5 mg of L-norepinephrine base.

- Use a controlled infusion system to achieve a precise estimate of the flow rate in drops per minute. The infusion should be performed in veins of upper limbs.

- The technique of ligature of the catheter should be avoided, if possible, because obstruction of blood flow around the tube may cause stasis and increased local concentration of norepinephrine.

- Do not use the injectable if it has a brown color or contains precipitate.

Overdose

Symptoms

Overdose causes severe hypertension with intense headache, photophobia, acute retrosternal pain, pharyngeal pain, intense pallor, and sweating, and vomiting.

Emergency treatment, antidotes

The recommended treatment for norepinephrine overdose includes:

• suspending the medication
• adequate fluid and electrolyte replacement therapy

for hypertension: if necessary, a α-adrenergic blocker can be administered intravenously with 5 to 10 mg of fentolamine.