N-Epi

Strength: Each ml contains norepinephrine bitartrate equivalent to norepinephrine base 1 mg.
Excipients/Inactive Ingredients: Sodium citrate 2H₂O, sodium chloride, sodium metabisulfite, anhydrous citric acid.

Pharmacotherapeutic group: Adrenergic and dopaminergic agents. ATC code: C01CA03.
Pharmacodynamics: Norepinephrine bitartrate functions as a peripheral vasoconstrictor (alpha-adrenergic action) and as an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action).
The vascular effects of noradrenaline (norepinephrine) 1:1000 in the doses usually 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. 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.
Pharmacokinetics: Absorption: Norepinephrine is ineffective orally, and subcutaneous absorption is poor. As a result, it is recommended that norepinephrine be administered only via the intravenous route. Following IV administration, the onset of activity is rapid, with a short duration of only 1 - 2 minutes after the infusion is discontinued.
Distribution: Norepinephrine localizes mainly in sympathetic nervous tissue. The drug crosses the placenta but not the blood-brain barrier.
Elimination: The pharmacologic actions of norepinephrine are terminated primarily by uptake and metabolism in sympathetic nerve endings. The drug is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglycol. Norepinephrine metabolites are excreted in urine primarily as the sulfate conjugates and, to a lesser extent, as the glucuronide conjugates. Only small quantities of norepinephrine are excreted unchanged.

For blood pressure control in acute hypotension.

Recommended dose: For blood pressure control in acute hypotension.
Adult: Blood volume depletion should always be corrected as fully as possible before any vasopressor is administered.
When, as an emergency measure, intraaortic pressures must be maintained to prevent cerebral or coronary artery ischemia, norepinephrine bitartrate can be administered before and concurrently with blood volume replacement.
Average dosage: Add a 4 ml ampoule (4 mg) of norepinephrine bitartrate to 1000 ml of a 5% dextrose containing solution. Each ml of this dilution contains 4 mcg of the base of norepinephrine bitartrate.
Give this solution by IV infusion. Insert a plastic IV catheter through a suitable bore needle well advanced centrally into the vein and securely fixed with adhesive tape.
An IV drip chamber or other suitable metering device is essential to permit an accurate estimation of the rate of flow in drops per minute. After observing the response to an initial dose of 2 ml to 3 ml (from 8 mcg to 12 mcg of base) per minute, adjust the rate of flow to establish and maintain a low normal blood pressure (usually 80 mmHg to 100 mmHg systolic) sufficient to maintain the circulation to vital organs.
In previously hypertensive patients, it is recommended that the blood pressure should be raised no more than 40 mmHg below the preexisting systolic pressure. The average maintenance dose ranges from 0.5 ml to 1 ml per min (from 2 mcg to 4 mcg of base).
High dosage: Great individual variation occurs in the dose required to attain and maintain an adequate blood pressure. In all cases, dosage of norepinephrine bitartrate should be titrated according to the response of the patient. Occasionally much larger or even enormous daily doses (as high as 68 mg base or 17 ampoules) may be necessary if the patient remains hypotensive, but occult blood volume depletion should always be suspected and corrected when present. 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 at a flow rate that would involve an excessive dose of the pressor agent per unit of time, a solution more dilute than 4 mcg per ml should be used. On the other hand, when large volumes of fluid are clinically undesirable, a concentration more than 4 mcg/ml may be necessary.
Duration of therapy: The infusion should be continued until adequate blood pressure and tissue perfusion are maintained without therapy. Infusions of norepinephrine bitartrate should be reduced gradually, avoiding abrupt withdrawal.
In some of the reported cases of vascular collapse due to acute Ml, treatment was required for up to 6 days.
Children: Not recommended. Safety and efficacy of norepinephrine in pediatric patients have not been established.
Elderly: See adult dosage. Norepinephrine infusions should not be administered into the veins of the legs in elderly patients.
Patients with hepatic impairment: No specific recommendations are available.
Patients with renal impairment: No specific recommendations are available.
Maximum dose: Adults: 30 mcg/min IV continuous infusion.
Elderly: 30 mcg/min IV continuous infusion.
Adolescents: 30 mcg/min IV continuous infusion.
Mode of administration: Norepinephrine bitartrate is a concentrated, potent drug which must be diluted in dextrose containing solutions prior to infusion, an infusion of norepinephrine bitartrate should be given into a large vein. The Injection is not to be used if its colour is pinkish or darker than slightly yellow or if it contains a precipitate.

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.

1) Norepinephrine is contraindicated in patients who are hypotensive due to blood volume deficit except during emergency to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed. If norepinephrine is continuously administered to maintain blood pressure in the absence of blood volume replacement, the following may occur: severe peripheral and visceral vasoconstriction, decreased renal perfusion and urine output, poor systemic blood flow despite "normal" blood pressure, tissue hypoxia and lactic acidosis.
2) Norepinephrine is contraindicated in patients with peripheral or mesenteric thrombosis due to the risk of increasing ischemia and extending the area of infarction, unless administration is necessary for a life-saving procedure.
3) Norepinephrine is contraindicated for use during cyclopropane and halothane anesthetics because of the risk of producing ventricular or tachycardia fibrillation.
4) Patients with profound hypoxia or hypercarbia can develop arrhythmias.

1. Norepinephrine injection should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOIs) or antidepressants of the triptyline or imipramine types because severe prolonged hypertension may result.
2. Norepinephrine injection contains sodium metabisulfite, a sulfite that may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

Avoid hypertension: Because of the potency of norepinephrine and because of varying response to pressor substances the possibility always exists that dangerously high blood pressure may be produced with overdoses of this pressor agent. It is desirable, therefore, to record the blood pressure every two minutes from the time administration is started until the desired blood pressure is obtained, then every five minutes if administration is to be continued.
Site of infusion: Whenever possible, infusions of norepinephrine should be given into a large vein, particularly an antecubital vein because when administered into this vein the risk of necrosis of the overlying skin from prolonged vasoconstriction is apparently very slight. Femoral vein can also be used. A catheter tie-in technique should be avoided, if possible since the obstruction to blood flow around the tubing may cause stasis and increased local concentration of the drug. Occlusive vascular diseases are more likely to occur in the lower than in the upper extremity. Therefore, one should avoid the veins of the leg in elderly patients or in those suffering from such disorders.
Extravasation: The infusion site should be checked frequently for free flow. Care should be taken to avoid extravasation of norepinephrine into the tissues, as local necrosis might ensue due to the vasoconstrictive action of the drug. To prevent sloughing and necrosis in areas in which extravasation has taken place, the area should be infiltrated as soon as possible with 10 ml to 15 ml of saline solution containing from 5 mg to 10 mg of phentolamine mesylate for injection USP, an adrenergic blocking agent. A syringe with a fine hypodermic needle should be used, with the solution being infiltrated liberally throughout the area, which is easily identified by its cold, hard, and pallid appearance. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours. Therefore, phentolamine should be given as soon as possible after the extravasation is noted.
Preexisting hyperthyroidism or hypertension: Because norepinephrine could exacerbate the underlying condition.
Use in Children: Safety and effectiveness in pediatric patients have not been established.

Pregnancy: Norepinephrine is classified as FDA pregnancy risk category C (Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus). Easily crosses the placenta, and may stimulate uterine contractions or constrict uterine blood flow, leading to fetal hypoxia.
Lactation: It is not known whether norepinephrine is excreted into human breast milk. Use caution when considering the use of norepinephrine in lactating women.

Serious adverse reactions: Cardiovascular: Cardiac arrest, Cardiac arrhythmia. Cardiac arrhythmias may arise when norepinephrine is used in conjunction with cardiac sensitising agents, and may be more likely in patients with hypoxia or hypercarbia.
Common adverse reactions: Cardiovascular: Hypertension may occur, which may be associated with bradycardia as well as headache and peripheral ischemia, including gangrene of the extremities.
Dermatologic: Extravasation of norepinephrine, especially with repeated injections or high infusion rates, can result in severe tissue damage and necrosis.
Gastrointestinal: Nausea, Vomiting.
Neurologic: Confusion, Headache, Tremor.
Psychiatric: Anxiety, Restlessness.
Renal: Urinary retention.
Respiratory: Dyspnea, respiratory difficulty.
CNS: Anxiety, transient headache.
Miscellaneous: Ischemic injury due to potent vasoconstrictor action and tissue hypoxia.
Prolonged administration 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 norepinephrine bitartrate injection 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 ischemic injury. Gangrene of extremities has been rarely reported.
Overdoses or conventional doses in hypersensitive persons (e.g. hyperthyroid patients) cause severe hypertension with violent headache, photophobia, stabbing retrosternal pain, pallor, intense sweating and vomiting.

Beta-Blockers: Beta-blockers directly antagonize the beta-agonist (i.e., cardiac-stimulating) effects of norepinephrine. Possible increased risk of severe hypertension and bradycardia when noradrenaline (norepinephrine) given with non-cardioselective beta-blockers.
Beta-Blockers: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting).
COMT Inhibitors: Drugs known to be metabolized by catechol-O-methyltransferase (COMT), such as norepinephrine, regardless of the route of administration, should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure. Effects of noradrenaline (norepinephrine) possibly enhanced by entacapone.
COMT Inhibitors: May decrease the metabolism of COMT Substrates.
Risk C: Monitor therapy.
MAO Inhibitors (moderate, theoretical): May enhance the vasopressor effect of norepinephrine. Norepinephrine bitartrate injection should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) because severe, prolonged hypertension may result.
Tricyclic Antidepressants: May enhance the vasopressor effect of norepinephrine. Norepinephrine bitartrate injection should be used with extreme caution in patients receiving antidepressants of the triptyline or imipramine types, because severe, prolonged hypertension may result.
Cyclopropane and halothane anesthetics: Increase cardiac autonomic irritability and therefore seem to sensitize the myocardium to the action of IV administered epinephrine or norepinephrine. Hence, the use of norepinephrine bitartrate injection during cyclopropane and halothane anesthesia is generally considered contraindicated because of the risk of producing ventricular tachycardia or fibrillation.

Store below 30°C and protect from light.

Vasoconstrictors

C01CA03 - norepinephrine ; Belongs to the class of adrenergic and dopaminergic cardiac stimulants excluding glycosides. Used in the treatment of hypotension.

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