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Levophed Bitartrate

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

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 Bitartrate

Shock

Used to produce vasoconstriction and cardiac stimulation as an adjunct to correct hemodynamic imbalances in the treatment of shock that persists after adequate fluid volume replacement.b (See Hypovolemia under Cautions.)

If severe peripheral vasoconstriction exists, norepinephrine may be ineffective and may have a deleterious effect by causing further reductions in plasma volume and blood flow to vital organs.b

Value of pressor therapy in shock, especially when due to septicemia, burns, trauma, or drug overdosage, is questionable, either because the effectiveness has not been proved or because vasoconstriction caused by the drug may adversely affect the patient.b

May be indicated if patient fails to respond to administration of fluids, a change in position, or other measures directed to the specific cause of shock such as anti-infectives in septicemia, epinephrine in anaphylactic shock, or specific antidotes and/or removal of the drug in cases of drug overdosage.b

May be considered in the treatment of drug-induced distributive shock or shock associated with calcium-channel or β-adrenergic blocking agent toxicity.100

Pressor therapy in overdosage of barbiturates or other sedatives is especially controversial; some clinicians have stated that the incidence of mortality may actually be increased when a pressor is given.b

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May be useful to control shock following pheochromocytomectomy, but shock generally can be prevented by maintenance of adequate blood volume and/or preoperative administration of an α-adrenergic blocking agent.b

May be used as an adjunct in the management of shock resulting from sympathectomy or poliomyelitis.b

Anaphylactic Shock

Epinephrine is the drug of choice in the emergency treatment of severe acute anaphylactic reactions, including anaphylactic shock.b

Once adequate ventilation is assured, maintenance of blood pressure in patients with anaphylactic shock may be achieved with other pressor agents, such as norepinephrine.b

MI

In hypotension associated with MI, cautious administration of norepinephrine may be of value and some clinicians consider it to be the pressor drug of choice.b

This type of shock generally has a poor prognosis even when pressor agents are used, and norepinephrine-induced increases in myocardial oxygen demand and the work of the heart may outweigh the beneficial effects of the drug.b

Cardiac arrhythmias due to norepinephrine are more likely to occur in patients with MI.b

CPR

May be used for ACLS as an adjunct to maintain adequate BP when severe hypotension (e.g., SBP <70 mm Hg) and low total peripheral resistance persist (unresponsive to less potent adrenergic drugs, including dopamine, methoxamine, or phenylephrine) and renal and cerebral perfusion remain inadequate after an effective heartbeat, palpable pulse, and ventilation have been established by other means.100 b

Exhibits both positive inotropic and vasoconstrictive activity; therefore, may be particularly useful in elevating systolic arterial pressures to 70–100 mm Hg.b Once such elevations are achieved, dopamine therapy can be initiated.b

Relatively contraindicated in patients with hypovolemia.100 b

Use cautiously in patients with ischemic heart disease because it may increase myocardial oxygen requirements.100 b

Hypotension during Anesthesia

May be used to treat hypotension occurring during spinal anesthesia, but other vasopressors having a longer duration of action and which can be administered IM such as metaraminol, methoxamine, or phenylephrine are more commonly used.b

May be used to treat hypotension occurring during general anesthesia; however, the possibility of cardiac arrhythmias should be considered.b (See Specific Drugs under Interactions.)

If a vasopressor is required, norepinephrine should not be used in obstetric patients (see Pregnancy under Cautions); ephedrine usually is preferred.b

Adjunct to Local Anesthesia

May be added to solutions of some local anesthetics to decrease the rate of vascular absorption of the anesthetic, thereby localizing anesthesia and prolonging the duration of anesthesia.b

Decreases risk of systemic toxicity due to the local anesthetic.b

Not as potent as epinephrine and must be used in higher concentrations to prolong local anesthetic effects; epinephrine is more commonly used for this purpose.b

GI Hemorrhage

Has been used with some success intraperitoneally or via a nasogastric tube as a hemostatic agent for severe upper GI bleeding.b

Pericardial Tamponade

Has been used to increase cardiac output by increasing ventricular emptying and temporarily increasing cardiac filling pressure in pericardial tamponade.b

Levophed Bitartrate 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.b

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

  • 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.b

  • Elevate BP to slightly less than the patient’s normal BP.b

  • In previously normotensive patients, maintain SBP at 80–100 mm Hg; in previously hypertensive patients, maintain SBP at 30–40 mm Hg below their preexisting BP.b

  • Very severe hypotension: Maintenance of even lower BP may be desirable if blood or fluid volume replacement has not been completed.b

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

  • 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.b

  • In some patients, additional administration of IV fluids may be necessary before norepinephrine can be discontinued.

  • Do not reinstate pressor therapy until the SBP falls to 70–80 mm Hg.b

Administration

Administer by IV infusion.b

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.b

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

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

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.b

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.b 100 (See Extravasation and also Extravasation Treatment under Cautions for discussion on the prevention and treatment of the adverse effects of extravasation.)

In prolonged therapy, change the injection site periodically.b

Dilution

Prior to administration, dilute the commercially available concentrate for injection with 5% dextrose injection, with or without sodium chloride.100 b

Concentration of norepinephrine and the infusion rate depend on the drug and fluid requirements of the individual patientb

Infusion solution usually prepared by adding 4 mg of norepinephrine (4 mL of the commercially available injection) to 1 L of 5% dextrose injection creating a resultant solution containing 4 mcg/mL;b a more dilute or concentrated solution may be prepared depending on the fluid volume requirements of the patient.100 b

Dosage

Available as norepinephrine bitartrate; dosage expressed in terms of norepinephrine (2 mg of norepinephrine bitartrate is equivalent to 1 mg of norepinephrine).100 b

Pediatric Patients

Shock

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

IV

Usually administered at a rate of 2 mcg/minute; alternatively, 2 mcg/m2 per minute.b

Pediatric Advanced Life Support (PALS) during CPR
IV

Infusion rate: 0.1–2 mcg/kg per minute; adjust to achieve the desired change in BP and perfusion.100 b

Adults

Shock

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

IV

Usual initial dosage: 8–12 mcg/minute; alternatively, some clinicians suggest initiating norepinephrine therapy at a dosage of 0.5–1 mcg/minute titrated to effect.b 100

Average adult maintenance dosage: 2–4 mcg/minute.b

Refractory Shock
IV

May require 8–30 mcg/minute.b

GI Hemorrhage
Intraperitoneal

8 mg of norepinephrine in 250 mL of 0.9% sodium chloride injection has been administered intraperitoneally to control upper GI bleeding.b

Nasogastric

8 mg of norepinephrine in 100 mL of 0.9% sodium chloride solution has been instilled through a nasogastric tube every hour for 6–8 hours, then every 2 hours for 4–6 hours to control upper GI bleeding; frequency of administration was then gradually reduced until the drug was discontinued.b

Special Populations

Geriatric Patients

Has not been evaluated systematically in those 65 years of age and older, but the manufacturers currently do not make specific dosage recommendations for geriatric patients.b

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.b

Cautions for Levophed Bitartrate

Contraindications

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

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

  • In conjunction with local anesthetics, use in fingers, toes, ears, nose, or genitalia is contraindicated.b

Warnings/Precautions

Warnings

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

Additional volume replacement also may be required during or after administration of norepinephrine, especially if hypotension recurs.b

Monitoring of central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia; in addition, monitoring of central venous or pulmonary arterial diastolic pressure is necessary to avoid overloading the cardiovascular system and precipitating CHF.b

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

Extravasation

Because severe local adverse effects (e.g., tissue necrosis, sloughing at injection site) may occur as a result of local vasoconstriction, extravasation of norepinephrine must be avoided.100 b

The site of infusion should be checked frequently for free flow and the infused vein should be observed for blanching.b

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

Avoid injection into leg veins, especially in geriatric patients or those with occlusive vascular diseases, arteriosclerosis, diabetes mellitus, or Buerger’s disease.b

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

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

Extravasation Treatment

If extravasation occurs, 10–15 mL of sodium chloride solution containing 5–10 mg of phentolamine mesylate should be infiltrated (using a syringe with a fine hypodermic needle) liberally throughout the affected area, which is identified by a cold, hard, and pallid appearance.100 b

Immediate and conspicuous local hyperemic changes occur if the area is infiltrated within 12 hours, but such treatment is ineffective when given >12 hours after extravasation; therefore, phentolamine should be administered as soon as possible after extravasation is noted.100 b

Addition of 5–10 mg of phentolamine to each L of infusion fluid containing norepinephrine may prevent sloughing of tissue, if extravasation occurs, without altering the pressor effects of norepinephrine; however, IV injection of phentolamine is not an effective antidote after extravasation has occurred.b

In severe hypotension after MI: Thrombosis in the infused vein and perivenous reactions and necrosis may be prevented by adding enough heparin to the norepinephrine infusion to supply 100–200 units of heparin per hour.b

Hypertensive or Hyperthyroid Patients

Risk of adverse reactions (e.g., photophobia, pallor, intense sweating, vomiting, retrosternal or pharyngeal pain, severe hypertension, cerebral hemorrhage, seizures, severe headache) in patients who are hypersensitive to the effects of norepinephrine (e.g., hyperthyroid patients).b Administer with caution to hypertensive or hyperthyroid patients.b

Peripheral or Mesenteric Vascular Thrombosis

Unless necessary as a life-saving procedure, do not use in patients with peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of infarction extended.b

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.b

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

Cardiovascular and Renal Effects

Can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion and therefore decreased urine output, tissue hypoxia, and metabolic acidosis; these effects are most likely to occur in hypovolemic patients.b

May cause plasma volume depletion which may result in perpetuation of the shock state or recurrence of hypotension when the drug is discontinued.b

Increases myocardial oxygen consumption and the work of the heart.b

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 palpitation and bradycardia as well as potentially fatal cardiac arrhythmias, including ventricular tachycardia, bigeminal rhythm, nodal rhythm, AV dissociation, and fibrillation.b

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

Specific Populations

Pregnancy

Category C.c

Lactation

Unknown whether norepinephrine is distributed into milk.b c Because of norepinephrine’s indications, use during breast-feeding is unlikely.c

Pediatric Use

Safety and efficacy not established.b

Geriatric Use

Has not been evaluated systematically in those ≥65 years of age, but the manufacturers currently do not make specific dosage recommendations for geriatric patients.b

If used in geriatric patients, the 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.b

Norepinephrine infusions should not be administered into leg veins in geriatric patients.b (See Extravasation under Cautions.)

Common Adverse Effects

Headache, weakness, dizziness, tremor, pallor, respiratory difficulty or apnea, precordial pain.b

Interactions for Levophed Bitartrate

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

Propranolol may be used to treat cardiac arrhythmias occurring during administration of norepinephrineb

Anesthetics, general (cyclopropane or halogenated hydrocarbons)

Concomitant use may result in arrhythmiasb

Concomitant use with cyclopropane or halogenated hydrocarbon general anesthetics generally contraindicatedb

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

Antidepressants, tricyclic (e.g., imipramine)

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

Use norepinephrine cautiously and in small dosesb

Antidepressants, MAO inhibitors

Risk of severe, prolonged hypertensionb

MAO is one of the enzymes responsible for norepinephrine metabolismb

Manufacturer states that norepinephrine should be administered with extreme caution to patients receiving an MAO inhibitor; however, some clinicians report that MAO inhibitors do not appear to potentiate effects of norepinephrine to a clinically important extentb

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 sulfate 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

Guanethidine

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 Bitartrate 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

Tight, light-resistant containers.b

Protect from light and air at 25°C (may be exposed to 15–30°C).b

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

  • Directly stimulates β-adrenergic receptors of the heart (β1-adrenergic receptors) but not those of the bronchi or peripheral blood vessels (β2-adrenergic receptors).b

  • Believed that α-adrenergic effects result from inhibition of the production of cyclic adenosine-3′,5′-monophosphate (AMP) by inhibition of the enzyme adenyl cyclase, whereas β-adrenergic effects result from stimulation of adenyl cyclase activity.b

  • Main effects of therapeutic doses are vasoconstriction and cardiac stimulation.b 100

  • Constricts both capacitance and resistance blood vessels by its effect on α-adrenergic receptors.b

  • Total peripheral resistance is increased, resulting in increased SBP and DBP.b Blood flow to vital organs, skin, and skeletal muscle is reduced.b

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

  • May reduce circulating plasma volume (especially with prolonged use) as a result of loss of fluid into extracellular spaces caused by postcapillary vasoconstriction.b

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

  • Although norepinephrine has fewer CNS effects than does epinephrine, restlessness, headache, and tremor may occur.

  • Can increase glycogenolysis and inhibit insulin release in the pancreas, resulting in hyperglycemia.b

  • Increased oxygen consumption and elevation of body temperature may occur.b

  • As a result of its effect on α-adrenergic receptors, norepinephrine may cause contraction of the pregnant uterus and constriction of uterine blood vessels; however, the vasoconstrictor effects may be overcome by an increase in maternal blood pressure.b

Advice to Patients

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

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

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

Preparations

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

* 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 Bitartrate

Hospira

Norepinephrine Bitartrate Injection

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 4, 2013. 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.

b. AHFS drug information 2007. McEvoy GK, ed. Norepinephrine. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1350-3.

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. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:862-6.

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