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Phenylephrine Hydrochloride

Pronunciation

Class: alpha-Adrenergic Agonists
VA Class: AU100
CAS Number: 61-76-7
Brands: Benadryl, Excedrin, Preparation H, Sudafed PE, Theraflu, Triaminic, Tylenol, Vicks

Introduction

Sympathomimetic amine that predominantly acts by a direct effect on α-adrenergic receptors.

Uses for Phenylephrine Hydrochloride

Shock

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

Individual hemodynamic abnormalities must be identified and monitored so that therapy can be adjusted as necessary.b

May be ineffective if severe peripheral vasoconstriction exists 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;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 overdosage. Drugs which also stimulate the myocardium (e.g., norepinephrine, metaraminol) are usually preferred to phenylephrine, especially in shock caused by myocardial infarction, septicemia, or surgical complications.b

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

May be useful when cardiac stimulation is undesirable (as in the treatment of hypotension occurring during general anesthesia with cyclopropane, halothane, or other agents that sensitize the myocardium to arrhythmias).b

May be used to treat hypotension or shock resulting from overdosage of or idiosyncratic reactions to certain drugs (e.g., adrenergic and ganglionic blocking agents, rauwolfia and veratrum alkaloids, phenothiazines).b

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

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Hypotension During Spinal Anesthesia

Has been used both for the prevention and treatment of hypotension resulting from spinal anesthesia, but some clinicians state that pure α-adrenergic agonists should not be used because they may further reduce cardiac output.b

Routine prophylactic use of any vasopressor in spinal anesthesia has been questioned because hypotension does not always occur during spinal anesthesia and treatment can readily be instituted if necessary; it has been suggested that vasopressors be administered prophylactically only in those cases in which a substantial decrease in BP is expected.b

Use of vasopressors to correct hypotension occurring during anesthesia in obstetrical patients is controversial; hypotension can usually be minimized by adequate hydration and changing the position of the patient so that the uterus does not compress the inferior vena cava; if a vasopressor is required, ephedrine is usually preferred.b

Prolongation of 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 effective as epinephrine in prolonging local anesthesia but may be preferred when cardiostimulation is undesirable.b

Paroxysmal Supraventricular Tachycardia

Administered IV to raise BP in order to terminate some attacks of paroxysmal supraventricular tachycardia, especially in patients who are also hypotensive or in shock.b

Administration of an anticholinesterase drug having a short duration of action (e.g., edrophonium chloride) may be safer.b

Nasal Congestion

Self-medication for temporary relief of nasal congestion associated with upper respiratory allergy (e.g., hay fever) or the common cold.114 124 However, efficacy of oral phenylephrine for this use has been questioned.115 125 126 127

Self-medication for temporary relief of sinus congestion and pressure.114 124

Used in fixed combination with other agents (e.g., acetaminophen, chlorpheniramine, dextromethorphan, diphenhydramine, guaifenesin, pheniramine) for temporary relief of nasal/sinus congestion and/or other symptoms (e.g., rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, cough) associated with seasonal or perennial allergic rhinitis, other upper respiratory allergies, or the common cold.133 134 135 136 137 138 139

Because of recent state and federal actions restricting OTC sale and purchase of preparations containing pseudoephedrine, ephedrine, or phenylpropanolamine (no longer commercially available in the US),109 110 111 112 some manufacturers have reformulated various OTC preparations by substituting phenylephrine for pseudoephedrine that was previously contained in these preparations.113 116

Labeled and has been used for self-medication for temporary relief of nasal congestion associated with sinusitis;114 117 however, efficacy data are lacking and/or controversial.117 118 119 In October 2005, FDA issued a final rule to remove this indication from labeling of OTC nasal decongestants.117 Compliance date for preparations with annual sales <$25,000 was October 11, 2007; compliance date for all other preparations was April 11, 2007.117

Hemorrhoids

Anorectal preparations (e.g., creams, gels, ointments, suppositories) containing phenylephrine hydrochloride are used topically or rectally to provide temporary symptomatic relief of external or internal hemorrhoids.101 102 103 104 105 106 107 108

When applied topically or rectally to the anorectal area, vasoconstrictors such as phenylephrine stimulate α-adrenergic receptors in the vascular beds102 with a resultant temporary constriction of arterioles and a modest and transient reduction in congestion (swelling) of hemorrhoidal tissues.101 102 108

May relieve anorectal pruritus, discomfort, and irritation, possibly in part secondary to some weak local anesthetic action; the mechanism of this local anesthetic effect is unknown.102 108

May relieve pruritus associated with histamine release.102 108

If minor bleeding is present, a clinician should be consulted promptly for advice since anorectal bleeding may be a sign of conditions ranging in seriousness from simple abrasions to cancer.108

Diagnosis of Heart Murmurs

IV phenylephrine has been used to increase BP as an aid in the diagnosis of heart murmurs.b

Phenylephrine Hydrochloride Dosage and Administration

General

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

  • Previously normotensive patients: SBP should be maintained at 80–100 mm Hg.b

  • Previously hypertensive patients: SBP should be maintained at 30–40 mm Hg below their usual BP.b

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

  • Do not leave patients receiving the drug by IV infusion unattended; the infusion flow rate must be closely monitored; check BP frequently, especially during IV administration.b

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

  • IV infusion discontinuance: Gradually slow the infusion rate and avoid abrupt withdrawal.b

  • Observe patient carefully so that therapy may be resumed if the BP falls too rapidly.b

  • Do not reinstate pressor therapy until the SBP falls to 70–80 mm Hg; some patients may require additional administration of IV fluids before discontinuation.b

Administration

Parenteral Administration

Vasopressor therapy: Administer by IM, sub-Q, or slow IV injection or IV infusion; route of administration determined by the needs of the individual patient.b

Patients who are in shock may require IV administration to ensure absorption.b Usually administered by IV infusion as a dilute solution.b

Direct IV injections are administered in treating paroxysmal atrial or nodal tachycardia or in emergencies requiring a strong, immediate pressor effect.b

Emergencies: May be administered by direct IV injection.b

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

Dilution

For convenience in administration by direct IV injection, 1 mL of the commercially available phenylephrine hydrochloride injection containing 10 mg/mL may be diluted with 9 mL of sterile water for injection to prepare a solution containing 1 mg/mL.b

For IV infusion, phenylephrine may be diluted with 5% dextrose or 0.9% sodium chloride injection.b

The concentration of phenylephrine and the infusion rate depend on the drug and fluid requirements of the individual patient. Infusion solutions are usually prepared by adding 10 mg of phenylephrine hydrochloride to 500 mL of diluent.

Oral Administration

Vasoconstrictor for nasal congestion: Administer orally alone114 124 or as a fixed-combination decongestant preparation.b

Place orally dissolving strip(s) on the tongue, where it rapidly dissolves and then can be swallowed.124

Topical and Rectal Administration

Vasoconstrictor for hemorrhoidal symptoms: Topical preparations are administered externally to the affected perianal area, and rectal preparations are administered externally to the affected perianal area and/or intrarectally.101 102 103 104 105 106 107 108

Apply topical preparations labeled for external use only externally to the affected area and do not administer inside the rectum by either using fingers or any mechanical device or applicator.101 102 103 105 107

Rectal preparations are labeled either for rectal use only (e.g., suppositories) or for external and/or intrarectal use only.101 102 104 106 107

When a special applicator such as a pile pipe or other mechanical device is used to administer the drug intrarectally, attach the applicator to the tube of drug and then lubricate the applicator well and gently insert into the rectum;101 102 104 cleanse the applicator thoroughly after each use and store according to the manufacturer’s instructions.104

Do not use such preparations if introduction of the applicator or device into the rectum causes additional pain; advise patients to consult a clinician promptly in such cases.101 102 104 107

Remove wrapper from suppositories prior to insertion into the rectum.101 102 106 107

Advise patients receiving the drug for the local management of hemorrhoids to cleanse the affected perianal area by patting with warm water and mild soap and rinsing thoroughly or with an appropriate cleansing wipe whenever practical.101 102 103 104 105 106 107

Dry the area by patting or blotting with toilet tissue or a soft cloth before application of the drug.101 102 103 104 105 106 107

Dosage

Because combinations and dosage strengths vary for fixed-combination preparations, consult manufacturer’s product labeling for appropriate dosage of the specific preparation.

Pediatric Patients

Administer the lowest effective dosage for the shortest possible time; when possible, small doses should be injected initially and subsequent doses determined by pressor response.b

Hypotension
Mild or Moderate
IM or Sub-Q

Children: 0.1 mg/kg or 3 mg/m2 IM or sub-Q; may give additional IM or sub-Q doses in 1–2 hours if needed.b

Hypotension During Spinal Anesthesia
Treatment
IM or Sub-Q

Children: 0.044–0.088 mg/kg IM or sub-Q to treat hypotension during spinal anesthesia.b

Nasal Congestion
Oral

Self-medication in children 2–5 years of age: 2.5 mg every 4 hours.124

Self-medication in children 6–11 years of age: 5 mg every 4 hours.124

Self-medication in children ≥12 years of age: Usually, 10 mg every 4 hours.114 b

May be administered in fixed combination with other drugs.b

Discontinue therapy if symptoms persist for >7 days or are accompanied by fever or if nervousness, dizziness, or insomnia occurs.114 124

Hemorrhoids
Temporary Relief
Topical or Rectal

Children ≥12 years of age: Self-medication with a cream, gel, ointment, or suppository containing 0.25% of the drug alone or in combination with other anorectal agents (e.g., protectants, local anesthetics, astringents, antipruritics, analgesics).101 102 103 104 105 106 107 108

Administer at bedtime, in the morning, and after bowel movements102 103 104 105 106 up to 4 times daily.101 102 103 104 105 106 107 108

Do not exceed the recommended dosage unless otherwise directed by a clinician.101 102 103 104 105 106 107 108

Anorectal dosage for self-medication of hemorrhoids should not exceed 2 mg daily (i.e., 0.5 mg 4 times daily).108

Adults

Administer the lowest effective dosage for the shortest possible time; when possible, small doses should be injected initially and subsequent doses determined by pressor response.b

Hypotension
Mild or Moderate
IM or Sub-Q

Usually, 2–5 mg; doses range from 1–10 mg.b

Initially, do not exceed 5 mg.b

IV

Usually, 0.2 mg by slow IV injection; doses range from 0.1–0.5 mg.b

Initial dose should not exceed 0.5 mg; doses may be given no more frequently than every 10–15 minutes.b

Severe Hypotension or Shock
IV

Administer as a dilute solution.b (See Parenteral Administration under Dosage and Administration.)

Usually administer at an initial rate of 0.1–0.18 mg/minute; after the BP stabilizes, 0.04–0.06 mg/minute is usually adequate.b

Rate of infusion is adjusted to maintain the BP at the desired level.b

To produce the desired pressor response, additional drug in increments of 10 mg or more may be added to the infusion solution and the rate of flow adjusted according to the response of the patient.b

Hypotensive emergencies: May be given IV in an initial dose of 0.2 mg; any subsequent dose should not exceed the previous dose by 0.1–0.2 mg and a single dose should not exceed 0.5 mg.b

Hypotension During Spinal Anesthesia
Prevention
IM or Sub-Q

Low spinal anesthesia: Usually, 2 mg.b

High spinal anesthesia: 3 mg may be necessary.b

Administer 3–4 minutes prior to the spinal anesthetic.b

Prolongation of Spinal Anesthesia
IV

Usually, 2–5 mg are added to the anesthetic solution.b

Vasoconstriction for Regional Anesthesia
IV

Optimally, the concentration of phenylephrine hydrochloride is 0.05 mg/mL (1:20,000).b

Solutions may be prepared for regional anesthesia by adding 1 mg of phenylephrine hydrochloride to each 20 mL of local anesthetic solution.b

Some pressor response can be expected when at least 2 mg is injected.b

Paroxysmal Supraventricular Tachycardia
IV

Initially, administer rapidly (within 20–30 seconds) by direct IV injection with a dose not exceeding 0.5 mg; increase subsequent doses in increments of 0.1–0.2 mg, depending on the BP response of the patient. b

Do not raise SBP above 160 mm Hg.b

Maximum single dose is 1 mg.b

Nasal Congestion
Oral

Self-medication: Usually, 10 mg every 4 hours.114 b May be administered in fixed combination with other drugs.b

Discontinue therapy if symptoms persist for >7 days or are accompanied by fever or if nervousness, dizziness, or insomnia occurs.114

Hemorrhoids
Temporary Relief
Topical or Rectal

Self-medication as a cream, gel, ointment, or suppository containing 0.25% of the drug alone or in combination with other anorectal agents (e.g., protectants, local anesthetics, astringents, antipruritics, analgesics).101 102 103 104 105 106 107 108

Administer at bedtime, in the morning, and after bowel movements102 103 104 105 106 up to 4 times daily.101 102 103 104 105 106 107 108

Do not to exceed the recommended dosage unless otherwise directed by a clinician.101 102 103 104 105 106 107 108

Anorectal dosage for self-medication of hemorrhoids should not exceed 2 mg daily (i.e., 0.5 mg 4 times daily).108

Prescribing Limits

Pediatric Patients

Nasal Congestion
Oral

Self-medication in children 2–5 years of age: Maximum 15 mg in any 24-hour period.124

Self-medication in children 6–11 years of age: Maximum 30 mg in any 24-hour period.124

Self-medication in children ≥12 years of age: Maximum 60 mg in any 24-hour period.114

Hemorrhoids (Temporary Relief)
Topical or Rectal

Children ≥12 years of age: Anorectal dosage for self-medication of hemorrhoids should not exceed 2 mg daily (i.e., 0.5 mg 4 times daily).108

Adults

Hypotension
Mild or Moderate
Sub-Q or IM

Initially, do not exceed 5 mg.b

IV

Initial dose should not exceed 0.5 mg; repeat doses no more frequently than every 10–15 minutes.b

Hypotension during Spinal Anesthesia (Prevention)
IM or Sub-Q

Hypotensive emergencies: May be given IV in an initial dose of 0.2 mg; any subsequent dose should not exceed the previous dose by 0.1–0.2 mg and a single dose should not exceed 0.5 mg.b

Paroxysmal Supraventricular Tachycardia
IV

Maximum single dose is 1 mg.b

Do not raise SBP above 160 mm Hg.b

Nasal Congestion
Oral

Self-medication: Maximum 60 mg in any 24-hour period.114

Hemorrhoids (Temporary Relief)
Topical or Rectal

Anorectal dosage for self-medication of hemorrhoids should not exceed 2 mg daily (i.e., 0.5 mg 4 times daily).108

Cautions for Phenylephrine Hydrochloride

Contraindications

  • Severe hypertension or ventricular tachycardia.b

  • Peripheral or mesenteric vascular thrombosis, because ischemia may be increased and the area of infarction extended.b

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

  • Severe coronary disease or cardiovascular disease (including MI) in the view of some clinicians.b

  • For self-medication of hemorrhoidal symptoms unless otherwise directed by a clinician: Cardiac disease, high BP, thyroid disease, diabetes mellitus, or difficulty in urination secondary to prostatic hyperplasia.101 102 103 104 105 106 107 108

  • Known hypersensitivity to phenylephrine or to any ingredient in the respective formulation.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 phenylephrine must not be used as sole therapy in hypovolemic patients.b

Additional volume replacement also may be necessary during or after administration of epinephrine, 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

Severe vasoconstrictive effects may be most likely to occur in hypovolemic patients.b

Hypoxia and Acidosis

Hypoxia and acidosis may reduce the effectiveness of phenylephrine and must be identified and corrected prior to or concurrently with administration of the drug.b

Concomitant Diseases

Administer with extreme caution to geriatric or hyperthyroid patients or those with bradycardia, partial heart block, myocardial disease, or severe arteriosclerosis.b

Administer parenterally with extreme caution if at all to hypertensive patients.b

If administered to patients with acute pancreatitis or hepatitis, the drug may increase ischemia in the liver or pancreas.b

Do not use for self-medication for nasal congestion in patients with thyroid disease, diabetes mellitus, hypertension, heart disease, or difficulty urinating because of prostatic hypertrophy without consulting a clinician.114 124

MAO Inhibitors and Antihypertensive Agents

Avoid use for self-medication for nasal congestion if currently receiving or have recently received (i.e., within 2 weeks) an MAO inhibitor.114 124

Consult a clinician before initiating self-medication with an anorectal preparation of the drug if they currently are receiving an antihypertensive agent or antidepressant (e.g., MAO inhibitor).101 102 103 104 105 106 107 108

Sensitivity Reactions

Sulfite Reactions

Some formulations of phenylephrine hydrochloride injection contain sulfites which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.b

Major Toxicities

Overdosage

Overdosage may cause hypertension, headache, seizures, cerebral hemorrhage, palpitation, paresthesia, or vomiting; headache may be a symptom of hypertension.b

Hypertension may be relieved by administration of an α-adrenergic blocking agent (e.g., phentolamine).b

General Precautions

Prolonged Administration

Prolonged administration of vasopressors has caused edema, hemorrhage, focal myocarditis, subpericardial hemorrhage, necrosis of the intestine, or hepatic and renal necrosis; these effects have generally occurred in patients with severe shock and it is not clear if the drug or the shock state itself was the cause.b

Combination Preparations

When used in combination with other drugs (e.g., acetaminophen, chlorpheniramine, dextromethorphan, diphenhydramine, guaifenesin, pheniramine), consider the cautions, precautions, and contraindications associated with all ingredients in the formulation.133 134 135 136 137 138 139 b

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

Systemic Effects

Injections may be followed by paresthesia in the extremities or a feeling of coolness in the skin.b

Cardiac Effects

When ≥2 mg is injected during regional local anesthesia, a pressor response may occur.b

Administration by rapid IV injection in the treatment of paroxysmal supraventricular tachycardia may result in overdosage with short paroxysms of ventricular tachycardia, ventricular extrasystoles, or a sensation of fullness in the head.b

Can cause severe bradycardia and decreased cardiac output.b

Decreased cardiac output may be especially harmful to elderly patients and/or those with initially poor cerebral or coronary circulation.b

Reduced Vital Organ Blood Flow

Can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion, and probably reduced urine output and metabolic acidosis.

Extravasation

May cause necrosis or sloughing of tissue if extravasation occurs during IV administration or following sub-Q administration.b

Anorectal Use

Based on observations with local use for nasal congestion, prolonged local use of excessive anorectal dosages of vasoconstrictors will likely lead to rebound vasodilation and congestion.108

Less commonly, prolonged local use of excessive anorectal dosages of vasoconstrictors can lead to anxiety and paranoia.108

Contact dermatitis has been reported following topical application of certain formulations of vasoconstrictors.108

Possibility that topical anorectal application of vasoconstrictors if absorbed systemically in adequate amounts could interact with MAO inhibitors resulting in potentiated hypertensive effects should be considered.108

For additional precautions associated with anorectal phenylephrine therapy, see Topical and Rectal Administration under Dosage and Administration.

Specific Populations

Pregnancy

Category C.132

Administration in late pregnancy or labor may cause fetal anoxia and bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.132 b

If a vasopressor is used in conjunction with oxytocic drugs, the vasopressor effect is potentiated and may result in potentially serious adverse effects.b (See Oxytocic Drugs under Interactions.)

Use during pregnancy only when clearly needed.b Other pressors (e.g., ephedrine) usually preferred.132

Lactation

Does not appear to be distributed to any great extent into breast milk.121 However, caution if used in nursing women.b

Pediatric Use

Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.128 129 Limited evidence of efficacy for these preparations in this age group; appropriate dosages not established.128 Therefore, FDA recommends not to use such preparations in children <2 years of age; safety and efficacy in older children currently under evaluation. Because children 2–3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations recently agreed to voluntarily revise the product labeling to state that such preparations should not be used in children <4 years of age. During the transition period, some preparations on pharmacy shelves will have the new recommendation (“do not use in children <4 years of age”), while others will have the previous recommendation (“do not use in children <2 years of age”). FDA recommends that parents and caregivers adhere to dosage instructions and warnings on the product labeling that accompanies the preparation and consult a clinician about any concerns.

Geriatric Use

Administer with extreme caution to geriatric patients.b

Common Adverse Effects

Systemic use: May cause restlessness, anxiety, nervousness, weakness, dizziness, precordial pain or discomfort, tremor, respiratory distress, pallor or blanching of the skin, or a pilomotor response.b

Anorectal use: In recommended dosages for local effect in anorectal disorders (e.g., hemorrhoids), adverse systemic effects of vasoconstrictors such as phenylephrine generally are minimal.108

Interactions for Phenylephrine Hydrochloride

Specific Drugs

Drug

Interaction

Comments

α-Adrenergic blocking agents (phentolamine mesylate, phenothiazine)

Vasopressor response to phenylephrine is decreased by prior administration of an α-adrenergic blocking agentb

β-Adrenergic blocking agents

Cardiostimulating effects of phenylephrine are blocked by prior administration of β-adrenergic blocking drugsb

Anesthetics, general (cyclopropane or halogenated hydrocarbon)

Cyclopropane or halogenated hydrocarbon general anesthetics increase cardiac irritability, may sensitize the myocardium to phenylephrine, and may result in arrhythmiasb

Use only with extreme caution or not at all with these general anestheticsb

Antidepressants, tricyclic

May potentiate the vasopressor effects of phenylephrineb

Atropine

Blocks the reflex bradycardia caused by phenylephrine and enhances the pressor response to phenylephrineb

Digoxin

Possibility that digoxin can sensitize the myocardium to the effects of sympathomimetic drugs should be consideredb

Ergot alkaloids

Excessive rise in BP may occur if phenylephrine is administered to patients receiving a parenteral injection of an ergot alkaloid such as ergonovine maleate132 b

Guanethidine

May potentiate the vasopressor effects of phenylephrineb

MAO inhibitors

Cardiac and pressor effects of phenylephrine are potentiated by prior administration of MAO inhibitors because metabolism of phenylephrine is reducedb

The potentiation is greater following oral administration of phenylephrine than after parenteral administration of the drug because reduction of the metabolism of phenylephrine in the intestine results in increased absorption of the drugb

Avoid oral administration of phenylephrine in patients receiving an MAO inhibitor. Parenteral administration of phenylephrine to these patients, if unavoidable, should be undertaken with extreme caution and initial doses should be small

Patients should consult a clinician before initiating anorectal phenylephrine therapy if they are receiving an MAO inhibitorb

Oxytocic drugs

The pressor effect of phenylephrine is potentiated132 b

If phenylephrine is used during labor and delivery to correct hypotension or is added to a local anesthetic solution, the obstetrician should be cautioned that some oxytocic drugs may cause severe persistent hypertension and that rupture of a cerebral blood vessel may occur during the postpartum period132 b

Phenothiazines

Phenothiazines have some α-adrenergic blocking effects; therefore, prior administration of a phenothiazine may reduce the pressor effect and duration of action of phenylephrineb

Sympathomimetic agents (epinephrine)

Combination products containing phenylephrine and a bronchodilator sympathomimetic agent should not be used concomitantly with epinephrine or other sympathomimetic agents because tachycardia or other serious arrhythmias may occurb

Phenylephrine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Completely absorbed following oral administration; undergoes extensive first-pass metabolism in the intestinal wall.121 122

Bioavailability following oral administration is approximately 38% relative to IV administration.121 122 Because of extensive first-pass metabolism, considerable interindividual and possibly intraindividual variation in oral bioavailability exists.121

Peak serum concentrations occur at 0.75–2 hours following oral administration of 1- or 7.8-mg dose.121 122

Given parenterally to achieve cardiovascular effects.b

Onset

IV administration: Pressor effect occurs almost immediately.b

IM administration: Pressor effect occurs within 10–15 minutes.b

Oral administration: Nasal decongestion may occur within 15 or 20 minutes.b

Duration

IV administration: Pressor effect persists for 15–20 minutes.b

IM administration: Pressor effect persists for 30 minutes to 1–2 hours.b

Oral administration: Nasal decongestion may persist for 2–4 hours.b

Distribution

Extent

Undergoes rapid distribution into peripheral tissues; may be stored in certain organ compartments.121 Pharmacologic effects are terminated at least partially by uptake into tissues.b

Penetration into the brain appears to be minimal.121

Not known if phenylephrine crosses the placenta.132

Does not appear to be distributed to any great extent into breast milk.121

Elimination

Metabolism

Undergoes extensive metabolism in the intestinal wall (first-pass) and in the liver.121 122

Principal routes of metabolism involve sulfate conjugation (principally in the intestinal wall) and oxidative deamination (by the enzyme MAO); glucuronidation also occurs to a lesser extent.121 122

Elimination Route

Excreted in urine (80–86%) mainly as metabolites; unchanged drug accounts for 2.6 or 16% of an oral or IV dose, respectively.121 122

Half-life

2–3 hours following oral or IV administration.121 122

Special Populations

Clinical data regarding effects of renal or hepatic impairment on phenylephrine pharmacokinetics are limited.121

Because of extensive first-pass metabolism in the intestinal wall, hepatic impairment unlikely to result in major changes following oral administration; however, phenylephrine pharmacokinetics may be substantially altered following IV administration.121

Stability

Storage

Oral

Strips, orally dissolving

20–25°C.124

Tablets

15–25°C in a dry place.114

Parenteral

Injection

Tight, light-resistant containers.b

Up to 30°C protected from light.b

Solutions diluted in 5% dextrose injection are stable for at least 48 hours at pH 3.5–7.5.b

Stable for at least 48 hours when diluted to 0.02 mg/mL with 5% sodium bicarbonate injection.b

Compatibility

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

Parenteral

Solution CompatibilityHID

Compatible

Dextrose–Ringer’s injection combinations

Dextrose–Ringer’s injection, lactated, combinations

Dextrose–saline combinations

Dextrose 2.5, 5 or, 10% in water

Ionosol products

Ringer’s injection

Ringer’s injection, lactated

Sodium bicarbonate 5%

Sodium chloride 0.45 or 0.9%

Sodium lactate (1/6) M

Drug Compatibility
Admixture CompatibilityHID

Compatible

Chloramphenicol sodium succinate

Chloramphenicol sodium succinate with sodium bicarbonate

Dobutamine HCl

Lidocaine HCl

Potassium chloride

Sodium bicarbonate

Y-site CompatibilityHID

Compatible

Amiodarone HCl

Anidulafungin

Argatroban

Bivalirudin

Caspofungin acetate

Cisatracurium besylate

Dexmedetomidine HCl

Doripenem

Etomidate

Famotidine

Fenoldopam mesylate

Haloperidol lactate

Hetastarch in lactated electrolyte injection (Hextend)

Levofloxacin

Micafungin sodium

Remifentanil HCl

Telavancin HCl

Vasopressin

Zidovudine

Incompatible

Furosemide

Variable

Propofol

Actions

  • Acts predominantly by a direct effect on α-adrenergic receptors; in therapeutic doses, the drug has no substantial stimulant effect on the β-adrenergic receptors of the heart (β1-adrenergic receptors) but substantial activation of these receptors may occur when larger doses are given.b

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

  • Does not stimulate β-adrenergic receptors of the bronchi or peripheral blood vessels (β2-adrenergic receptors).b

  • Main effect of therapeutic doses of phenylephrine is vasoconstriction.b

  • Constricts resistance and, to a lesser degree, capacitance blood vessels by its effects on α-adrenergic receptors.

  • Total peripheral resistance is increased, resulting in increased SBP and DBP.b

  • Venous return to the heart may be decreased; however, phenylephrine increases venous pressure slightly.b

  • Blood flow to vital organs, skin, and probably skeletal muscle is reduced.b

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

  • Constriction of renal blood vessels by phenylephrine decreases renal blood flow.b

  • Local vasoconstriction and hemostasis also occur following topical application or infiltration of phenylephrine into tissues.b

  • Following oral administration, constriction of blood vessels in the nasal mucosa may relieve nasal congestion.b

  • Main effect on the heart is bradycardia, which results from increased vagal activity occurring as a reflex to increased arterial BP.b

  • Bradycardia occurs after parenteral administration of usual therapeutic doses and may also result from overdosage via oral inhalation.b

  • Attacks of paroxysmal atrial or nodal tachycardia may be ended by the decrease in sympathetic cardioaccelerator tone and increase in parasympathomimetic cardiodecelerator tone.b

  • Constricts coronary blood vessels but increases coronary blood flow, probably as a result of increased systemic BP.b

  • In therapeutic doses, causes little if any CNS stimulation but may cause nervousness, restlessness, anxiety, dizziness, and tremor in some patients, especially after overdosage.b

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

Advice to Patients

  • Importance of advising patients not to exceed the recommended dosage unless otherwise directed by a clinician.101 102 103 104 105 106 107 108

  • Importance of informing patient to consult a clinician before using for self-medication of nasal congestion if they have been diagnosed with thyroid disease, diabetes mellitus, hypertension, heart disease, or difficulty urinating because of prostatic hypertrophy.114 124

  • Importance of discontinuing self-medication of nasal congestion and consulting a clinician if symptoms persist >7 days or are accompanied by fever or if nervousness, dizziness, or insomnia develops during therapy.114 124

  • Importance of informing patients not to exceed 2 mg daily (i.e., 0.5 mg 4 times daily) for the anorectal dosage for self-medication of hemorrhoids.108

  • Importance of informing patients to consult a clinician if the anorectal condition worsens or does not improve within 7 days or if bleeding occurs.101 102 103 104 105 106 107

  • Importance of informing patients that when a special applicator such as a pile pipe or other mechanical devise is used to administer the drug intrarectally, the applicator should be attached to the tube of drug and then the applicator should be lubricated well and gently inserted into the rectum;101 102 104 cleanse the applicator thoroughly after each use and store according to the manufacturer’s instructions.104

  • Importance of advising patients to not use and to consult a clinician promptly if introduction of the applicator or device into the rectum causes additional pain.101 102 104 107

  • Importance of informing patients to remove wrapper from suppositories prior to insertion into the rectum.101 102 106 107

  • Importance of informing patients receiving the drug for the local management of hemorrhoids to cleanse the affected perianal area by patting with warm water and mild soap and rinsing thoroughly or with an appropriate cleansing wipe whenever practical;101 102 103 104 105 106 107 dry the area by patting or blotting with toilet tissue or a soft cloth before application of the drug.101 102 103 104 105 106 107

  • Importance of informing patients to consult a clinician promptly for advice if minor bleeding is present since anorectal bleeding may be a sign of conditions ranging in seriousness from simple abrasions to cancer.108

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.131

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.131

  • Importance of informing patients of other important precautionary information.131 (See Cautions.)

Preparations

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

Many prescription cough, cold, and allergy preparations commercially available in the US have not been approved by the US Food and Drug Administration (FDA).500 Because of the potentially serious health risks associated with unapproved preparations, FDA announced on March 3, 2011, that it would take enforcement action (e.g., seizure, injunction, other judicial or administrative proceeding) against any currently marketed and listed unapproved cough, cold, and allergy preparation manufactured on or after June 1, 2011 or shipped on or after August 30, 2011.500 For additional information and for a complete list of unapproved cough, cold, and allergy preparations affected by this FDA notice, see FDA website ().

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

Phenylephrine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg

Sudafed PE Congestion

McNeil

Parenteral

Injection

10 mg/mL*

Phenylephrine Hydrochloride Injection

Topical

Cream

0.25% with Glycerin 14.4%, Petrolatum 15%, and Pramokine 1%

Preparation H

Pfizer

Gel

0.25% with Witch Hazel 50%

Preparation H

Pfizer

Ointment

0.25% with Mineral Oil 14%, and Petrolatum 71.9%

Preparation H

Pfizer

Suppository

0.25% with Cocoa Butter 85.39%

Preparation H

Pfizer

Phenylephrine Hydrochloride Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, (liquid-filled)

5 mg with Acetaminophen 325 mg and Dextromethorphan Hydrobromide 10 mg

Vicks DayQuil Cold & Flu Relief LiquiCaps

Procter & Gamble

For Solution

10 mg/packet with Acetaminophen 325 mg/packet and Pheniramine Maleate 20 mg/packet

Theraflu Cold & Sore Throat

Novartis

10 mg/packet with Acetaminophen 650 mg/packet and Dextromethorphan Hydrobromide 20 mg

Theraflu Daytime Severe Cold & Cough

Novartis

10 mg/packet with Acetaminophen 650 mg/packet and Pheniramine Maleate 20 mg/packet

Theraflu Flu & Sore Throat

Novartis

10mg/packet with Acetaminophen 650 mg/packet and Diphenhydramine Hydrochloride 25 mg

Theraflu Nighttime Severe Cold & Cough

Novartis

10 mg/packet with Dextromethorphan Hydrobromide 20 mg/packet and Pheniramine Maleate 20 mg/packet

Theraflu Cold & Cough

Novartis

Solution

5 mg/15 mL with Acetaminophen 325 mg/15 mL and Dextromethorphan Hydrobromide 10 mg/15 mL

Theraflu Warming Relief Daytime Severe Cold & Cough

Novartis

Vicks DayQuil Cold & Flu Relief

Procter & Gamble

5 mg/15 mL with Acetaminophen 325 mg/15 mL and Diphenhydramine Hydrochloride 12.5 mg/15 mL

Theraflu Warming Relief Flu & Sore Throat

Novartis

Theraflu Warming Relief Nighttime Severe Cold & Cough

Novartis

2.5 mg/5 mL with Acetaminophen 160 mg/5 mL and Chlorpheniramine Maleate 1 mg/5 mL

Children’s Tylenol Plus Cold

McNeil

2.5 mg/5 mL with Acetaminophen 160 mg/5 mL and Chlorpheniramine Maleate 1 mg/5 mL, and Dextromethorphan Hydrobromide 5 mg/5mL

Children’s Tylenol Plus Multi-Symptom Cold

McNeil

2.5 mg/5 mL with Acetaminophen 160 mg/5 mL and Diphenhydramine Hydrochloride 12.5 mg/5 mL

Children’s Tylenol Plus Cold & Allergy

McNeil

2.5 mg/5 mL with Chlorpheniramine Maleate 1 mg/5 mL

Triaminic Cold & Allergy

Novartis

2.5 mg/5 mL with Dextromethorphan Hydrobromide 5 mg/5mL

Children’s Sudafed PE Cold & Cough

McNeil

Triaminic Day Time Cold & Cough

Novartis

2.5 mg/5mL with Diphenhydramine Hydrochloride 6.25 mg/5 mL

Triaminic Night Time Cold & Cough

Novartis

2.5 mg/5 mL with Guaifenesin 50 mg/5mL

Triaminic Chest & Nasal Congestion

Novartis

Strips, orally dissolving

2.5 mg with Dextromethorphan 3.67 mg (equivalent to Dextromethorphan Hydrobromide 5 mg)

TriaminicThin Strips Day Time Cold & Cough

Novartis

5 mg with Diphenhydramine Hydrochloride 12.5 mg

Triaminic Thin Strips Night Time Cold & Cough

Novartis

Tablets

5 mg with Acetaminophen 325 mg, Chlorpheniramine Maleate 2 mg, and Dextromethorphan Hydrobromide 10 mg

Theraflu Warming Relief Caplets Nighttime Multi-Symptom Cold

Novartis

5 mg with Acetaminophen 325 mg and Dextromethorphan Hydrobromide 10 mg

Theraflu Warming Relief Caplets Daytime Multi-Symptom Cold

Novartis

10 mg with Chlorpheniramine Maleate 4 mg

Sudafed PE Sinus + Allergy

McNeil

Tablets, film-coated

5 mg with Acetaminophen 325 mg

Excedrin Sinus Headache

Novartis

Sudafed PE Pressure + Pain Caplets

McNeil

5 mg with Acetaminophen 325 mg, Chlorpheniramine Maleate 2 mg, and Dextromethorphan Hydrobromide 10 mg

Tylenol Cold Head Congestion Nighttime Cool Burst Caplets

McNeil

5 mg with Acetaminophen 325 mg and Dextromethorphan Hydrobromide 10 mg

Tylenol Cold Head Congestion Daytime Cool Burst Caplets

McNeil

5 mg with Acetaminophen 325 mg, Dextromethorphan Hydrobromide 10 mg, and Guaifenesin 100 mg

Sudafed PE Cold + Cough Caplets

McNeil

5 mg with Acetaminophen 325 mg and Diphenhydramine Hydrochloride 12.5 mg

Sudafed PE Severe Cold Caplets

McNeil

5 mg with Guaifenesin 200 mg

Sudafed PE Non-Drying Sinus Caplets

McNeil

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Donatussin 10-2-15-100MG/5ML Syrup (LASER PHARMACEUTICALS): 473/$36.25 or 1419/$108.75

Duraphen Forte 30-30-1200MG 12-hr Tablets (KOWA PHARMACEUTICALS AMERICA): 100/$135.98 or 300/$375.97

Duratuss AC 12 15-12.5-15MG/5ML Suspension (VICTORY PHARMA): 473/$215.99 or 1419/$609.96

Promethazine VC Plain 6.25-5MG/5ML Syrup (QUALITEST): 473/$39.99 or 1419/$109.97

R-Tanna 9-25MG Tablets (PRASCO LABORATORIES): 30/$39.99 or 90/$109.97

Rynatan 9-25MG Tablets (MEDA PHARMACEUTICALS): 30/$122.99 or 90/$349.97

Rynatan Pediatric 4.5-5MG/5ML Suspension (MEDA PHARMACEUTICALS): 120/$105.99 or 360/$299.96

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

Only references cited for selected revisions after 1984 are available electronically.

101. Food and Drug Administration. Anorectal drug products for over-the-counter human use. [21 CFR Part 346] 2003 April 1.

102. Boyd EL, Berardi RR. Anorectal disorders. In: Berardi RR, DeSimone EM II, Newton GD eds. Handbook of nonprescription drugs: an interactive approach to self-care. Washington, DC: American Pharmaceutical Association; 2002:361-80.

103. Wyeth. Preparation H (cream) prescribing information. From Wyeth website (). 2003.

104. Wyeth. Preparation H (ointment) prescribing information. From Wyeth website (). 2003.

105. Wyeth. Preparation H (gel) prescribing information. From Wyeth website (). 2003.

106. Wyeth. Preparation H (suppositories) prescribing information. From Wyeth website (). 2003.

107. Food and Drug Administration. Anorectal drug products for over-the-counter human use: final monograph. [21 CFR Parts 310, 346, and 369] Fed Regist. 1990; 55:31776.

108. Food and Drug Administration. Anorectal drug products for over-the-counter human use: establishment of a monograph. Fed Regist. 1980; 45:35576-35677.

109. National Association of Chain Drug Stores. State methamphetamine precursor laws. From the NACDS website (). Accessed October 3, 2005.

110. National Alliance for Model State Drug Laws. Methamphetamine Information. From the Alliance website (). Accessed October 3, 2005.

111. United States. Cong. Senate. 109th Congress. S. 103, A Bill to Amend the Controlled Substances Act (title VII of the Departments of Commerce and Justice, Science, and Related Agencies Appropriations Act, 2006 [HR 2862]). From the Library of Congress website (). Accessed October 3, 2005.

112. Anon. Senate approves anti-meth bill. CBS News, 2005 Sep 10. From CBS news website ()

113. Novartis, East Hanover, NJ: Personal communication.

114. Pfizer. Sudafed PE nasal decongestant (phenylephrine hydrochloride) tablets product information. From Pfizer website (). Accessed October 17, 2005.

115. Hendeles L. Selecting a decongestant. Pharmacotherapy. 1993; 13:129S-134S. [IDIS 323175] [PubMed 7507590]

116. Pfizer, Morris Plains, NJ: Personal communication.

117. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; amendment of final monograph for over-the-counter nasal decongestant drug products. 21 CFR Parts 310 and 341. Final rule. [Docket No. 2004N-0289] Fed Regist. 2005; 70:58974-7.

118. Spector SL, Bernstein IL, Li JT et al for the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Parameters for the diagnosis and management of sinusitis. J Allergy Clin Immunol. 1998; 102(Suppl):S107-44. [PubMed 9847450]

119. American Academy of Pediatrics: subcommittee on management of sinusitis and committee on quality improvement. Clinical practice guideline: Management of sinusitis. Pediatrics. 2001; 108:798-808. [PubMed 11533355]

120. Benninger MS, Anon J, Mabry RL. The medical management of rhinosinusitis. Otolaryngol Head Neck Surg. 1997; 117(Suppl):S41-9. [PubMed 9334787]

121. Kanfer I, Dowse R, Vuma V. Pharmacokinetics of oral decongestants. Pharmacotherapy. 1993; 13(Suppl):116-28S.

122. Hengstmann JH, Goronzy J. Pharmacokinetics of 3H-phenylephrine in man. Eur J Clin Pharmacol. 1982; 21:335-41. [PubMed 7056280]

124. Novartis. Triaminic (phenylephrine hydrochloride) Thin Strips Cold product information. From Novartis Triaminic website (). Accessed October 18, 2006.

125. Hendeles L, Hatton RC. Oral phenylephrine: an ineffective replacement for pseudoephedrine?. J Allergy Clin Immunol. 2006; 118:279-80. [PubMed 16815167]

126. Eccles R. Phenylephrine an ineffective replacement for pseudoephedrine in response to the methamphetamine problem in the USA. BMJ [serial online]. 2006 May 22. Available at (). Accessed 2006 Sep 7.

127. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; tentative final monograph for over-the-counter nasal decongestant drug products. 21 CFR Part 341. Notice of proposed rulemaking. [Docket No. 76N-052N] Fed Regist. 1985; 50:2220-41.

128. Srinivasan A, Budnitz D, Shehab N et al. Infant deaths associated with cough and cold medications—two states, 2005. MMWR Morb Mortal Wkly Rep. 2007; 56:1-4. [PubMed 17218934]

129. Food and Drug Administration. Cough and cold medications in children less than two years of age. Rockville, MD; 2007 Jan 12. From FDA website ().

130. Anon. Makers pull cold medicines sold for infants. CNN News, 2007 Oct 11. From CNN.com website ().

131. Ligand Pharmaceuticals. Avinza (morphine sulfate) extended-release capsules prescribing information. San Diego, CA. 2003 Feb.

132. 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; 2002:1113-1114.

133. Pfizer Consumer Healthcare. Benadryl Allergy & Cold (acetaminophen, diphenhydramine hydrochloride, and phenylephrine hydrochloride) caplets patient information. From Pfizer Consumer Healthcare website (). Accessed 2008 Feb 21.

134. McNeil-PPC, Inc. Tylenol Allergy Multi-Symptom Nighttime (acetaminophen, diphenhydramine hydrochloride, and phenylephrine hydrochloride) Cool Burst caplets patient information. From McNeil-PPC website (). Accessed 2008 Feb 21.

135. Pfizer Consumer Healthcare. Benadryl-D Allergy & Sinus (diphenhydramine hydrochloride and phenylephrine hydrochloride) tablets patient information. From Pfizer Consumer Healthcare website (). Accessed 2008 Feb 25.

136. Procter & Gamble. Vicks Dayquil Cold & Flu (acetaminophen, dextromethorphan hydrobromide, and phenylephrine hydrochloride) Liquicaps patient information. From Procter & Gamble website (). Accessed 2008 Feb 25.

137. Novartis Consumer Health, Inc. Theraflu Nighttime Severe Hot Liquid (acetaminophen, pheniramine maleate, and phenylephrine hydrochloride) patient information. From Novartis website (). Accessed 2008 Feb 25.

138. McNeilPPC, Inc. Tylenol Cold Multi-Symptom Nighttime Cool Burst Liquid (acetaminophen, dextromethorphan hydrobromide, doxylamine succinate, and phenylephrine hydrochloride) patient information. From McNeil website (). Accessed 2008 Feb 25.

139. McNeil-PPC, Inc. Tylenol Cold Multi-Symptom Nighttime Cool Burst caplets (acetaminophen, chlorpheniramine maleate, dextromethorphan hydrobromide, and phenylephrine hydrochloride) patient information. From McNeil website (). Accessed 2008 Feb 25.

500. Food and Drug Administration. Drugs for human use; unapproved and misbranded oral drugs labeled for prescription use and offered for relief of symptoms of cold, cough, or allergy, enforcement action dates. Notice. [Docket No. FDA-2011-N-0100] Fed Regist. 2011; 76:11794-8.

b. AHFS drug information 2004. McEvoy GK, ed. Phenylephrine. Bethesda, MD: American Society of Health-System Pharmacists; 2004:1273–7.

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; 2013:939-41.

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