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Levophed

Pronunciation

Generic Name: Norepinephrine Bitartrate
Class: alpha- and beta-Adrenergic Agonists
VA Class: AU100
CAS Number: 69815-49-2

Warning(s)

  • Extravasation Risk
  • Phentolamine is the local antidote for peripheral ischemia resulting from extravasation of norepinephrine.101

  • Phentolamine should be given as soon as possible after extravasation is noted.101

  • Infiltrate the affected area (using a syringe with a fine hypodermic needle) liberally throughout as soon as possible with 10–15 mL of 0.9% sodium chloride injection containing 5–10 mg of phentolamine mesylate (an α-adrenergic blocking agent) to prevent sloughing and necrosis in ischemic areas.101

  • Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.101

Introduction

Norepinephrine is identical to the endogenous catecholamine that is synthesized in the adrenal medulla and in sympathetic nervous tissue; norepinephrine predominantly acts by a direct effect on α-adrenergic receptors.b

Uses for Levophed

Acute Hypotensive States

Used as adjunctive therapy to produce vasoconstriction and maintain BP in the management of certain acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, MI, septicemia, blood transfusion, drug reactions).101 153 154 157 162 163

Pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes.b Correct blood volume depletion as fully as possible before administration.b

Norepinephrine is considered drug of choice when a vasopressor is indicated in patients with septic shock; if adequate BP not achieved, epinephrine may be added or used as an alternative.153 155 158 If necessary, vasopressin may be given in conjunction with norepinephrine to further increase BP or reduce dosage requirements of norepinephrine.153 155

Also used to provide vasopressor support in other types of shock (e.g., cardiogenic, hemorrhagic), generally as a temporary measure until underlying cause can be treated.152 157 158 159 160 162

In patients who are hypotensive from blood volume deficits, manufacturer states to use norepinephrine only as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed.101

Early revascularization is standard of care in patients with cardiogenic shock; individualize use of vasopressors in this setting.161 162

Has been used to treat hypotension during spinal anesthesia; however, other vasopressors with a longer duration (e.g., phenylephrine) more commonly used.b

Advanced Cardiovascular Life Support

Used adjunctively in the management of cardiac arrest to restore and maintain adequate BP after an effective heartbeat and ventilation have been established by other means.100 101

High-quality CPR and defibrillation are the only proven interventions to increase survival to hospital discharge in ACLS.400 401 Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.400 401

Principal goal of pharmacologic therapy during cardiac arrest is to facilitate the return of spontaneous circulation (ROSC), and epinephrine is the drug of choice for this use.400 401 Vasoactive drugs such as norepinephrine may be used for hemodynamic support following resuscitation.403 404

Levophed Dosage and Administration

General

  • Observe the effect of the initial dose on BP carefully and adjust the rate of flow to establish and maintain the desired BP.101

  • Do not leave the patient unattended; must closely monitor the infusion flow rate.101

  • Check BP every 2 minutes from the time the norepinephrine infusion is started until the desired effect is achieved, then every 5 minutes while the drug is being infused.101

  • Elevate BP to a low normal level to maintain circulation to vital organs.101

  • In previously normotensive patients, maintain SBP at 80–100 mm Hg; in previously hypertensive patients, maintain SBP at no more than 40 mm Hg below their preexisting BP.101

  • Continue therapy until adequate BP and tissue perfusion are maintained.101

  • When discontinuing therapy, slow infusion rate gradually and avoid abrupt withdrawal; observe patient carefully so that therapy may be resumed if the BP falls too rapidly.101

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion using an infusion pump or other apparatus to control the rate of flow.101

Infuse into the antecubital vein if possible, although the femoral vein may also be used.101 (See Extravasation under Cautions.)

Administer through a plastic catheter inserted deep into the vein.101

A catheter tie-in technique should be avoided if possible because obstruction of blood flow around the tubing may cause stasis and increased local concentration of the drug.101

Should not be administered in the same IV line as alkaline solutions, which may inactivate the drug.100

Care must be taken to avoid extravasation because local necrosis may result. 101 (See Extravasation under Cautions.)

Dilution

Must dilute commercially available concentrate for injection with a dextrose-containing solution (5% dextrose injection, with or without 0.9% sodium chloride injection); dilution with 0.9% sodium chloride injection alone is not recommended.101

Concentration of norepinephrine and the infusion rate depend on the drug and fluid requirements of the individual patient.b

Infusion solution usually prepared by adding 4 mg of norepinephrine (4 mL of the commercially available injection) to 1 L of a 5% dextrose-containing solution to produce a concentration of 4 mcg/mL; a more dilute or concentrated solution may be prepared depending on the fluid requirements of the patient.101

Dosage

Available as norepinephrine bitartrate; dosage expressed in terms of norepinephrine.101

Pediatric Patients

Acute Hypotensive States
IV

If norepinephrine is used in pediatric patients, some clinicians have recommended an initial infusion rate of 0.05–0.1 mcg/kg per minute, titrated to effect (up to a maximum of 2 mcg/kg per minute).170

ACLS
IV

For postresuscitation stabilization in pediatric patients, an infusion rate of 0.1–2 mcg/kg per minute, adjusted based on patient response, has been used.403

Adults

Acute Hypotensive States
IV

Usual initial dosage: 8–12 mcg/minute; alternatively, some clinicians have suggested initial dosage of 0.5–1 mcg/minute, titrated to effect.100 101 b

Adjust rate of flow to establish and maintain desired BP.101 (See General under Dosage and Administration.)

Administer in the lowest effective dosage for the shortest possible time.b

Average adult maintenance dosage: 2–4 mcg/minute; however, there is wide variability in dosage range.101 158

A few hypotensive patients have required much larger dosages (as much as 68 mg daily).101 Patients with refractory shock may require 8–30 mcg/minute.b

ACLS
IV

If norepinephrine is used adjunctively to restore and maintain adequate BP during cardiac resuscitation, the manufacturer states to follow same dosage guidelines as for the treatment of acute hypotensive states.101 (See Acute Hypotensive States under Dosage and Administration.)

Special Populations

Hepatic Impairment

No specific dosage recommendations.101

Renal Impairment

No specific dosage recommendations.101

Geriatric Patients

If used in geriatric patients, initial dosage usually should be at the low end of the dosage range and caution should be exercised since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group than in younger patients.101

Cautions for Levophed

Contraindications

  • Generally contraindicated during anesthesia with cyclopropane or halogenated hydrocarbon general anesthetics.101 (See Specific Drugs under Interactions.)

  • Use in patients who are hypotensive from blood volume deficits except as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed.101

  • Use in patients with mesenteric or peripheral vascular thrombosis, unless clinically necessary as a life-saving procedure.101

  • Use in patients with profound hypoxia or hypercapnia may be contraindicated.101 (See Arrhythmias under Cautions.)

Warnings/Precautions

Warnings

Severe Hypertension

To avoid the potential for dangerously high BP, monitor BP closely during administration.101 Headache may be a symptom of hypertension due to overdosage.101

Hypovolemia

Pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes.b Correct blood volume depletion as fully as possible before administration.b

May be used in an emergency as an adjunct to fluid volume replacement or as a temporary supportive measure to maintain coronary and cerebral artery perfusion until volume replacement therapy can be completed, but norepinephrine must not be used as sole therapy in hypovolemic patients.b

Concomitant Drugs

Administer with extreme caution in patients receiving an MAO inhibitor or a triptyline- or imipramine-type antidepressant because severe, prolonged hypertension may result.101 (See Interactions.)

Extravasation

Because severe local adverse effects (e.g., tissue necrosis, sloughing at injection site) may occur as a result of local vasoconstriction, must avoid extravasation.101 (See Boxed Warning.)

Check site of infusion frequently for free flow and monitor infused vein for blanching.101

Risk of tissue damage is apparently very slight if infused through a plastic catheter deep into an antecubital vein.101

Avoid injection into leg veins, especially in geriatric patients or those with occlusive vascular diseases (e.g., arteriosclerosis, atherosclerosis, Buerger’s disease).101

Impairment of circulation and sloughing of tissue may also occur without obvious extravasation.101

If blanching is observed in the infused vein or if therapy is to be prolonged, consider changing the injection site periodically.101

Sensitivity Reactions

Sulfite Sensitivity

Formulations of norepinephrine bitartrate injection contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.101

General Precautions

Prolonged Administration

Has caused decreased cardiac output, edema, hemorrhage, focal myocarditis, subpericardial hemorrhage, necrosis of the intestine, or hepatic and renal necrosis.b Generally occurs in patients with severe shock and it is not clear if the drug or the shock state itself was the cause.b

Vasoconstriction

Can cause severe peripheral and visceral vasoconstriction, reducing blood flow and tissue perfusion to vital organs and resulting in possible tissue hypoxia, lactic acidosis, and ischemic injury; these effects are most likely to occur in hypovolemic patients if plasma volumes are not adequately corrected.101

Cardiovascular Effects

May cause plasma volume depletion, which may result in hypotension when the drug is discontinued in the absence of blood volume replacement.101

Cardiac output may be decreased following prolonged use of the drug or administration of large doses because venous return to the heart may be diminished because of increased peripheral vascular resistance; decreased cardiac output may be especially harmful to elderly patients or those with initially poor cerebral or coronary circulation.b

Arrhythmias

May cause bradycardia (probably a reflex response to increased BP) as well as potentially fatal cardiac arrhythmias, including ventricular tachycardia and ventricular fibrillation.101

Arrhythmias are especially likely to occur in patients with severe hypoxia, or hypercapnia, or those receiving other drugs that may increase cardiac irritability such as cyclopropane or halogenated hydrocarbon general anesthetics.101 (See Specific Drugs under Interactions.)

Hypoxia, Hypercapnia, and Acidosis

Hypoxia, hypercapnia, and acidosis may reduce the effectiveness and/or increase the incidence of adverse effects of norepinephrine, and must be identified and corrected prior to or concurrently with administration of the drug.b

Specific Populations

Pregnancy

Category C.101 Use during pregnancy only if clearly indicated.101

Lactation

Not known whether norepinephrine is distributed into milk.101 Use caution.101

Pediatric Use

Safety and efficacy not established.101

Geriatric Use

Insufficient experience in patients ≥65 years of age.101 (See Geriatric Patients under Dosage and Administration.)

Do not infuse into leg veins in geriatric patients.101 (See Extravasation under Cautions.)

Common Adverse Effects

May cause headache, anxiety, arrhythmias, bradycardia, respiratory difficulty, ischemic injury, or extravasation at the infusion site.101

Interactions for Levophed

Specific Drugs

Drug

Interaction

Comments

α-Adrenergic blocking agents (e.g., phentolamine)

Decreased pressor response in animals; however, interaction appears unlikely in humansb

β-Adrenergic blocking agents (e.g., propranolol)

Concomitant use may result in higher elevations of BP because of blockade of any β-mediated arteriolar dilationb

Cardiac stimulating effects of norepinephrine may be antagonizedb

Anesthetics, general (cyclopropane or halogenated hydrocarbons)

Concomitant use may result in arrhythmias101

Concomitant use with cyclopropane or halogenated hydrocarbon general anesthetics generally contraindicated101

If a pressor drug is required concomitantly with these general anesthetics, use one with minimal cardiac stimulating effects (i.e., phenylephrine)b

Antidepressants, tricyclic (e.g., imipramine)

May potentiate the pressor effects of norepinephrine, resulting in severe, prolonged hypertension101

Manufacturer states to use concomitantly with extreme caution101

Antidepressants, MAO inhibitors

Risk of severe, prolonged hypertension101

Manufacturer states to use concomitantly with extreme caution101

Antihistamines (especially diphenhydramine, tripelennamine, and dexchlorpheniramine)

May potentiate pressor effects of norepinephrine, resulting in severe, prolonged hypertensionb

Use norepinephrine cautiously and in small dosesb

Atropine

Atropine blocks the reflex bradycardia caused by norepinephrine and enhances the pressor response to norepinephrineb

Diuretics (e.g., furosemide)

May decrease arterial responsiveness to pressor drugsb

Ergot alkaloids, parenteral

May potentiate the pressor effects of norepinephrine, resulting in severe, prolonged hypertensionb

Use norepinephrine cautiously and in small dosesb

Methyldopa

May potentiate the pressor effects of norepinephrine, resulting in severe, prolonged hypertensionb

Use norepinephrine cautiously and in small dosesb

Levophed Pharmacokinetics

Absorption

Bioavailability

Oral: Destroyed in the GI tract.b

Sub-Q: Poorly absorbed.b

Onset

IV: Pressor response occurs rapidly.b

Duration

Short; pressor action stops within 1–2 minutes after the infusion is discontinued.b

Distribution

Extent

Localizes mainly in sympathetic nervous tissue.b

Crosses the placenta.b c Does not cross the blood-brain barrier.b

Not known if distributes into milk.b c

Elimination

Metabolism

Via the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and MAO.b

Pharmacologic actions are terminated mainly by uptake and metabolism in sympathetic nerve endings.b

Major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive.b

Elimination Route

Metabolites are excreted in urine mainly as the sulfate conjugates and, to a lesser extent, as the glucuronide conjugates; only small quantities of norepinephrine are excreted unchanged.b

Stability

Storage

Parenteral

Injection

20–25°C; protect from light.101

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

IV infusion: Dilute norepinephrine with 5% dextrose injection with or without sodium chloride to protect against loss of potency caused by oxidation during IV infusion; do not use sodium chloride injection alone.b 100

Following dilution with 5% dextrose, IV infusions containing norepinephrine 2.5 or 4 mcg/mL have been reported to be stable for at least 24 hours at room temperature if the pH is approximately 5.6.b

Norepinephrine solutions containing 2.5 mcg/mL in 5% dextrose have been reported to lose 5% of their potency in 6 hours at pH 6.5 and in 4 hours at pH 7.5.b

Use caution if diluted with 5% dextrose injections with a pH of >5.5–6 or if the drug is mixed with alkaline additives such as sodium bicarbonate, barbiturates, or alkaline buffered antibiotics which will result in pH >6; these solutions should be used immediately after preparation.b

Should not be administered in the same IV line as alkaline solutions, which may inactivate the drug.100

Administer whole blood or plasma, if indicated during therapy with norepinephrine, separately or via a Y-tube.b

Solution CompatibilityHID

Compatible

Amino acids 4.25%, dextrose 25%

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Amikacin sulfate

Calcium chloride

Calcium gluconate

Ciprofloxacin

Dimenhydrinate

Dobutamine HCl

Heparin sodium

Hydrocortisone sodium succinate

Magnesium sulfate

Meropenem

Methylprednisolone sodium succinate

Multivitamins

Potassium chloride

Succinylcholine chloride

Verapamil HCl

Incompatible

Aminophylline

Sodium bicarbonate

Variable

Ranitidine HCl

Y-site CompatibilityHID

Compatible

Amiodarone HCl

Anidulafungin

Argatroban

Bivalirudin

Caspofungin acetate

Ceftaroline fosamil

Cisatracurium besylate

Clonidine HCl

Dexmedetomidine HCl

Diltiazem HCl

Dobutamine HCl

Dopamine HCl

Doripenem

Epinephrine HCl

Esmolol HCl

Famotidine

Fenoldopam mesylate

Fentanyl citrate

Furosemide

Haloperidol lactate

Heparin sodium

Hetastarch in lactated electrolyte injection (Hextend)

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyethyl starch 130/0.4 in sodium chloride 0.9%

Labetalol HCl

Lorazepam

Meropenem

Micafungin sodium

Midazolam HCl

Milrinone lactate

Morphine sulfate

Mycophenolate mofetil HCl

Nicardipine HCl

Nitroglycerin

Potassium chloride

Propofol

Ranitidine HCl

Remifentanil HCl

Sodium nitroprusside

Telavancin HCl

Vasopressin

Vecuronium bromide

Incompatible

Insulin, regular

Variable

Pantoprazole sodium

Actions

  • Acts predominantly by a direct effect on α-adrenergic receptors.b

  • Also stimulates β1-adrenergic receptors but not β2-adrenergic receptors.b

  • Main therapeutic effect is a clinically important increase in mean arterial pressure (MAP), with minimal change in heart rate or cardiac output.101 153 156

  • Constricts both arterial and venous blood vessels through its effect on α-adrenergic receptors.b

  • Systemic vascular resistance is increased, resulting in increased BP.b

  • Induces vasoconstriction in most vascular beds, potentially reducing blood flow to the renal, splanchnic, and cutaneous vasculature.101 152 154 158

  • Local vasoconstriction caused by the drug may result in hemostasis and/or necrosis.b

  • May reduce circulating plasma volume (especially with prolonged use).b

  • Acts on β1-adrenergic receptors in the heart, producing a positive inotropic effect on the myocardium.b 100

Advice to Patients

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.101

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.101

  • Importance of informing patients of other important precautionary information.101 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Norepinephrine Bitartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, concentrate, for IV infusion

1 mg (of norepinephrine) per mL*

Levophed

Hospira

Norepinephrine Bitartrate Injection

AHFS DI Essentials. © Copyright 2016, Selected Revisions June 29, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I): IV1-211.

101. Hospira. Levophed (norepinephrine bitartrate injection) prescribing information. Lake Forest, IL; 2009 Nov.

152. Spahn DR, Bouillon B, Cerny V et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013; 17:R76. [PubMed 23601765]

153. Dellinger RP, Levy MM, Rhodes A et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013; 39:165-228. [PubMed 23361625]

154. De Backer D, Biston P, Devriendt J et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010; 362:779-89. [PubMed 20200382]

155. Cawcutt KA, Peters SG. Severe sepsis and septic shock: clinical overview and update on management. Mayo Clin Proc. 2014; 89:1572-8. [PubMed 25444488]

156. Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2014; 370:583. [PubMed 24499231]

157. Bouglé A, Harrois A, Duranteau J. Resuscitative strategies in traumatic hemorrhagic shock. Ann Intensive Care. 2013; 3:1. [PubMed 23311726]

158. Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med. 2011; 183:847-55. [PubMed 21097695]

159. Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation. 2008; 117:686-97. [PubMed 18250279]

160. Sperry JL, Minei JP, Frankel HL et al. Early use of vasopressors after injury: caution before constriction. J Trauma. 2008; 64:9-14. [PubMed 18188092]

161. American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, O'Gara PT et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 61:e78-140. [PubMed 23256914]

162. Amsterdam EA, Wenger NK, Brindis RG et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 64:e139-228. [PubMed 25260718]

163. Gamper G, Havel C, Arrich J et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2016; 2:CD003709. [PubMed 26878401]

165. Brown RS, Rhodus NL. Epinephrine and local anesthesia revisited. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005; 100:401-8. [PubMed 16182160]

166. Council on Clinical Affairs, American Academy of Pediatric Dentistry. Guideline on Use of Local Anesthesia for Pediatric Dental Patients. Pediatr Dent. 2015 Sep-Oct; 37:71-7. [PubMed 26531078]

167. van der Bijl P, Victor AM. Adverse reactions associated with norepinephrine in dental local anesthesia. Anesth Prog. 1992; 39:87-9. [PubMed 1308379]

170. Tschudy MM, Arcara KM, eds. The Harriet Lane handbook: a manual for pediatric house officers. 19th ed. Philadelphia, PA: Saunders; 2012:884.

400. Link MS, Berkow LC, Kudenchuk PJ et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015; 132(18 Suppl 2):S444-64. [PubMed 26472995]

401. Neumar RW, Otto CW, Link MS et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010; 122(18 Suppl 3):S729-67. [PubMed 20956224]

402. de Caen AR, Berg MD, Chameides L et al. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015; 132(18 Suppl 2):S526-42. [PubMed 26473000]

403. Kleinman ME, Chameides L, Schexnayder SM et al. Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010; 122(18 Suppl 3):S876-908. [PubMed 20956230]

404. Peberdy MA, Callaway CW, Neumar RW et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010; 122(18 Suppl 3):S768-86. [PubMed 20956225]

b. AHFS drug information 2017. McEvoy GK, ed. Norepinephrine. Bethesda, MD: American Society of Health-System Pharmacists; 2017.

c. Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002:1014.

pdh. Schilling McCann JA, Publisher. Pharmacists drug handbook. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins and American Society of Health-System Pharmacists; 2003.

HID. McEvoy GK, ed. Handbook on injectable drugs. 18th ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2015:878-82.

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