*In adult patients undergoing surgical procedures with either neuraxial [[anesthesia]] or [[general anesthesia]]:
:*50 mcg to 250 mcg by intravenous bolus administration. The most frequently reported initial bolus dose is 50 mcg or 100 mcg.
:*0.5 mcg/kg/min to 1.4 mcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal.
=====Septic or Other Vasodilatory Shock=====
*No bolus.
*0.5 mcg/kg/min to 6 mcg/kg/min by intravenous continuous infusion, titrated to [[blood pressure]] goal. Doses above 6 mcg/kg/min do not show significant incremental increase in blood pressure.
=====Uveitis=====
*Posterior Synechiae: Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be used in patients with [[uveitis]] when synechiae are present or may develop. The formation of synechiae may be prevented by the use of this solution and atropine or other [[cycloplegics]] to produce wide dilation of the pupil. For recently formed posterior [[synechiae]] one drop of Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be applied to the upper surface of the cornea and be repeated as necessary, not to exceed three times. Treatment may be continued the following day, if necessary. Atropine sulfate and the application of hot compresses should also be used if indicated.
=====Glaucoma=====
*Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be used with miotics in patients with open angle glaucoma. It reduces the difficulties experienced by the patient because of the small field produced by [[miosis]], and still it permits and often supports the effect of the miotic in lowering the intraocular pressure in open angle glaucoma. Hence, there may be marked improvement in visual acuity after using Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% in conjunction with miotic drugs.
=====Mydriasis Induction=====
*Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be used effectively to increase [[mydriasis]] with homatropine hydrobromide, [[cyclopentolate]] hydrochloride, [[tropicamide]] hydrochloride and atropine sulfate.
*One drop of the preferred cycloplegic is placed in each eye, followed in 5 minutes by one drop of Phenylephrine Hydrochloride Ophthalmic Solution, 2.5%. Since adequate [[cycloplegia]] is achieved at different time intervals after the instillation of the necessary number of drops, different cycloplegics will require different waiting periods to achieve adequate [[cycloplegia]].
<!--Off-Label Use and Dosage (Adult)-->
<!--Guideline-Supported Use (Adult)-->
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Non–Guideline-Supported Use (Adult)-->
|offLabelAdultNoGuideSupport======Hypotension, During anesthesia; Prophylaxis=====
*In women undergoing elective cesarean section with [[spinal anesthesia]], phenylephrine reduced the incidence of [[hypotension]] when used with ephedrine as prophylaxis.<ref name="pmid11575540">{{cite journal| author=Mercier FJ, Riley ET, Frederickson WL, Roger-Christoph S, Benhamou D, Cohen SE| title=Phenylephrine added to prophylactic ephedrine infusion during spinal anesthesia for elective cesarean section. | journal=Anesthesiology | year= 2001 | volume= 95 | issue= 3 | pages= 668-74 | pmid=11575540 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11575540 }} </ref>
*0.2 to 0.4 mg phenylephrine.<ref name="pmid884795">{{cite journal| author=Waxman MB, Wald RW| title=Termination of ventricular tachycardia by an increase in cardiac vagal drive. | journal=Circulation | year= 1977 | volume= 56 | issue= 3 | pages= 385-91 | pmid=884795 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=884795 }} </ref>
=====Priapism=====
*1 mg phenylephrine bolus followed by continuous intracavernosal phenylephrine infusion of 2 mg/hour.<ref name="pmid2627645">{{cite journal| author=Buckley JF, Chapple CR, McNicholas T| title=Continuous infusion of phenylephrine in the treatment of papaverine-induced priapism. | journal=Br J Urol | year= 1989 | volume= 64 | issue= 6 | pages= 654-5 | pmid=2627645 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2627645 }} </ref>
=====Regional anesthesia; Adjunct=====
*Phenylephrine 0.125% to combinations of tetracaine 0.5% plus glucose 7.5% or 0.75%.<ref name="pmid8922770">{{cite journal| author=Sumi M, Sakura S, Sakaguchi Y, Saito Y, Kosaka Y| title=Comparison of glucose 7.5% and 0.75% with or without phenylephrine for tetracaine spinal anaesthesia. | journal=Can J Anaesth | year= 1996 | volume= 43 | issue= 11 | pages= 1138-43 | pmid=8922770 | doi=10.1007/BF03011841 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8922770 }} </ref>
<!--Pediatric Indications and Dosage-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|fdaLIADPed======Perioperative Hypotension=====
*0.5 mg to 1 mg per every 25 pounds of body weight SUBQ or IM.
=====Mydriasis Induction=====
*For a “one application method,” Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be combined with one of the preferred rapid acting cycloplegics to produce adequate [[cycloplegia]].
<!--Off-Label Use and Dosage (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
*Phenylephrine 200 mcg (in 2 doses of 100 mcg each).<ref name="pmid4025769">{{cite journal| author=Jacobson L, Turnquist K, Masley S| title=Wolff-Parkinson-White syndrome. Termination of paroxysmal supraventricular tachycardia with phenylephrine. | journal=Anaesthesia | year= 1985 | volume= 40 | issue= 7 | pages= 657-60 | pmid=4025769 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4025769 }} </ref>
<!--Contraindications-->
|contraindications=* Phenylephrine Hydrochloride Injection should not be used in patients with severe [[hypertension]], [[ventricular tachycardia]] or in patients who are [[hypersensitive]] to it or to any of the components.
<!--Warnings-->
|warnings=====Precautions====
*Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension
:*Because of its pressor effects, phenylephrine hydrochloride can precipitate [[angina]] in patients with severe [[arteriosclerosis]] or history of [[angina]], exacerbate underlying [[heart failure]], and increase pulmonary arterial pressure.
*Bradycardia
:*Phenylephrine hydrochloride can cause severe [[bradycardia]] and decreased [[cardiac output]].
*Risk in Patients with Autonomic Dysfunction
:*The pressor response to [[adrenergic]] drugs, including phenylephrine, can be increased in patients with [[autonomic dysfunction]], as may occur with [[spinal cord injuries]].
*Skin and Subcutaneous Necrosis
:*Extravasation of phenylephrine can cause [[necrosis]] or sloughing of tissue.
*Pressor Effect with Concomitant Oxytocic Drugs
:*Oxytocic drugs potentiate the pressor effect of [[sympathomimetic]] pressor amines including phenylephrine hydrochloride, with the potential for [[hemorrhagic stroke]].
*Allergic Reactions
:*This product contains sodium metabisulfite, a sulfite that may cause [[allergic]]-type reactions, including [[anaphylactic]] symptoms and life-threatening or less severe [[asthmatic]] episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
*Peripheral and Visceral Ischemia
:*Phenylephrine hydrochloride can cause excessive peripheral and visceral [[vasoconstriction]] and [[ischemia]] to vital organs, particularly in patients with extensive [[peripheral vascular disease]].
*Renal Toxicity
:*Phenylephrine hydrochloride can increase the need for renal replacement therapy in patients with [[septic shock]]. Monitor renal function.
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
|clinicalTrials=*The following adverse reactions associated with the use of phenylephrine hydrochloride were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
[[Diaphoresis]], [[pallor]], [[piloerection]], skin blanching, skin [[necrosis]] with extravasation
=====Vascular disorders=====
[[Hypertensive crisis]]
<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
<!--Drug Interactions-->
|drugInteractions=* Agonists
:*The pressor effect of phenylephrine hydrochloride is increased in patients receiving:
:**[[Monoamine oxidase inhibitors]] (MAOI), such as [[selegiline]].
:**β-adrenergic blockers
:**α-2 adrenergic agonists, such as [[clonidine]]
:**[[Steroids]]
:**[[Tricyclic antidepressants]]
:**[[Norepinephrine]] transport inhibitors, such as [[atomoxetine]]
:**[[Ergot]] alkaloids, such as methylergonovine maleate
:**Centrally-acting sympatholytic agents, such as [[guanfacine]] or [[reserpine]]
:**[[Atropine]] sulfate
*Antagonists
:*α-adrenergic blocking agents, including [[phenothiazines]] (e.g., [[chlorpromazine]]) and [[amiodarone]] block phenylephrine and are in turn blocked by phenylephrine.
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category C'''
*Animal reproduction studies have not been conducted with phenylephrine. It is also not known whether phenylephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenylephrine should be given to a pregnant woman only if clearly needed.
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=*If vasopressor drugs are either used to correct [[hypotension]] or added to the [[local anesthetic]] solution, the obstetrician should be cautioned that some oxytocic drugs may cause severe persistent [[hypertension]] and that even a rupture of a cerebral blood vessel may occur during the postpartum period.
|useInNursing=*It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when phenylephrine hydrochloride is administered to a nursing woman.
|useInPed=*To combat [[hypotension]] during [[spinal anesthesia]] in children, a dose of 0.5 mg to 1 mg per 25 pounds of body weight, administered subcutaneously or intramuscularly, is recommended.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=*In patients with [[end stage renal disease]] (ESRD) undergoing [[hemodialysis]], dose-response data indicates increased responsiveness to phenylephrine. Consider using lower doses of phenylephrine hydrochloride in [[ESRD]] patients.
|useInHepaticImpair=*In patients with liver [[cirrhosis]] [Child Pugh Class A (n=3), Class B (n=5) and Class C (n=1)], dose-response data indicate decreased responsiveness to phenylephrine. Consider using larger doses than usual in hepatic impaired subjects.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
<!--Administration and Monitoring-->
|administration=*Oral
*Intravenous
*Intramuscular
*Subcutaneous
*Ophthalmic
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
<!--IV Compatibility-->
|IVCompat=*Preparing a 100 mcg/mL Solution of Bolus Intravenous Administration
:*For bolus intravenous administration, withdraw 10 mg (1 mL of a 10 mg/mL concentration) of phenylephrine injection and dilute with 99 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. This will yield a final concentration of 100 mcg/mL. Withdraw an appropriate dose from the 100 mcg/mL solution prior to bolus intravenous administration.
*Preparing a Solution for Continuous Intravenous Infusion
:*For continuous intravenous infusion, withdraw 10 mg (1 mL of 10 mg/mL concentration) of phenylephrine hydrochloride injection and add to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (providing a final concentration of 20 mcg/mL).
<!--Overdosage-->
|overdose====Acute Overdose===
====Signs and Symptoms====
* Overdosage may induce ventricular [[extrasystole]] and short paroxysms of [[ventricular tachycardia]], a sensation of fullness in the head and tingling of the extremities.
*The oral LD50 in the rat is 350 mg/kg, in the mouse 120 mg/kg.
====Management====
*Should an excessive elevation of blood pressure occur, it may be immediately relieved by an α-adrenergic blocking agent (e.g. [[phentolamine]]).
===Chronic Overdose===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
|mechAction=* Phenylephrine hydrochloride produces [[vasoconstriction]] that lasts longer than that of [[epinephrine]] and [[ephedrine]]. Responses are more sustained than those to epinephrine, lasting 20 minutes after intravenous and as long as 50 minutes after subcutaneous injection. Its action on the heart contrasts sharply with that of [[epinephrine]] and [[ephedrine]], in that it slows the heart rate and increases the stroke output, producing no disturbance in the rhythm of the pulse.
*Phenylephrine is a powerful postsynaptic alpha-receptor stimulant with little effect on the beta receptors of the heart. In therapeutic doses, it produces little if any stimulation of either the spinal cord or cerebrum. A singular advantage of this drug is the fact that repeated injections produce comparable effects.
|structure=* Phenylephrine hydrochloride is a vasoconstrictor and pressor drug chemically related to epinephrine and ephedrine. Phenylephrine hydrochloride is a synthetic sympathomimetic agent in sterile form for parenteral injection. Chemically, phenylephrine hydrochloride is (-)-m-Hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrochloride, and has the following structural formula:
'''Phenylephrine''' or '''Neo-Synephrine''' is an [[α-adrenergic receptor]] [[agonist]] used primarily as a [[decongestant]], as an agent to dilate the [[pupil]] and to increase [[blood pressure]]. Phenylephrine has recently been marketed as a substitute for [[pseudoephedrine]], (e.g. [[Pfizer]]'s ''Sudafed (Original Formulation)'') but there are recent claims that oral phenylephrine may be no more effective as a decongestant than placebo. <Ref name="UFL">[http://news.ufl.edu/2006/07/19/decongensant/ UF press release on the Hendles letter]</ref>
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
==Uses==
*Each mL contains: Phenylephrine Hydrochloride 10 mg; Sodium Chloride 3.5 mg; Sodium Citrate Dihydrate 4 mg; Citric Acid Monohydrate 1 mg; Sodium Metabisulfite 2 mg; Water for Injection q.s. pH adjusted with Sodium Hydroxide and/or Hydrochloric Acid if necessary. pH 3.0-6.5.
===Decongestant===
Phenylephrine is used as a decongestant, available as an oral medicine or as a nasal spray. Phenylephrine is now the most common [[Over-the-counter substance|over-the-counter]] (OTC) decongestant; [[oxymetazoline]] is a more common nasal spray. [[Pseudoephedrine]] was historically more common, although its notoriety as a [[methamphetamine]] precursor has led some governments to restrict its sale.
Oral phenylephrine is extensively [[metabolism|metabolised]] by [[monoamine oxidase]] [http://www.pharmgkb.org/do/serve?objId=975&objCls=DrugProperties], an [[enzyme]] which is present in the [[gastrointestinal tract]] and the liver. Therefore, compared to orally-taken pseudoephedrine, it has a reduced and variable [[bioavailability]] of only up to 38 percent [http://www.pharmgkb.org/do/serve?objId=975&objCls=DrugProperties] [http://www.medsafe.govt.nz/Profs/Class/mccMin25Nov2004.htm], and is therefore less effective than a nasal decongestant. Because phenylephrine is a direct selective α-adrenergic [[receptor agonist]], it does not cause the release of endogenous [[Norepinephrine|noradrenaline]] like pseudoephedrine does. Therefore, phenylephrine is less likely to cause side-effects like [[central nervous system]] stimulation, [[insomnia]], [[anxiety]], irritability and restlessness.
<!--Pharmacodynamics-->
|PD=*The predominant actions of phenylephrine are on the [[cardiovascular]] system. Parenteral administration causes a rise in systolic and diastolic pressures in man and other species. Accompanying the pressor response to phenylephrine is a marked reflex [[bradycardia]] that can be blocked by [[atropine]]; after [[atropine]], large doses of the drug increase the heart rate only slightly. In man, [[cardiac output]] is slightly decreased and peripheral resistance is considerably increased. Circulation time is slightly prolonged, and venous pressure is slightly increased; venous constriction is not marked. Most vascular beds are constricted; renal splanchnic, cutaneous and limb blood flows are reduced but coronary blood flow is increased. Pulmonary vessels are constricted, and pulmonary arterial pressure is raised.
Some popular [[Common cold|cold]] remedies containing phenylephrine: Canada's hot lemon Neocitran, the United Kingdom's [[Lemsip]], and the United States' [[Alka-Seltzer]] Cold Effervescent formula, [[Sudafed]] PE Non-Drowsy Nasal Decongestant, [[Robitussin]] CF, Tylenol Sinus, and [[DayQuil]] Capsules.
*The drug is a powerful [[vasoconstrictor]] with properties very similar to those of [[norepinephrine]] but almost completely lacking the [[chronotropic]] and [[inotropic]] actions on the heart. Cardiac irregularities are seen only very rarely even with large doses.
As a nasal spray, phenylephrine is available in 1% and 0.5% concentrations. It suffers some [[rebound effect|rebound]] congestion effects, although to a lesser degree than [[oxymetazoline]].
<!--Pharmacokinetics-->
|PK=*Following an intravenous infusion of phenylephrine hydrochloride, the effective half-life was approximately 5 minutes. The steady-state volume of distribution (340 L) exceeded the body volume by a factor of 5, suggesting a high distribution into certain organ compartments. The average total serum clearance (2095 mL/min) was close to one-third of the cardiac output.
===Mydriatic===
*A mass balance study showed that phenylephrine is extensively metabolized by the liver with only 12% of the dose excreted unchanged in the urine. Deamination by monoamino oxidase is the primary metabolic pathway resulting in the formation of the major metabolite (m-hydroxymandelic acid) which accounts for 57% of the total administered dose.
Phenylephrine is used as an eye drop to dilate the pupil to facilitate visualization of the retina. It is often used in combination with [[tropicamide]]. Narrow angle [[glaucoma]] is a [[contraindication]] to phenylephrine use.
===Vasopressor===
<!--Nonclinical Toxicology-->
Phenylephrine is sometimes used as a [[vasopressor]] to increase the blood pressure in unstable patients with hypotension. Such use is more common in anesthesia or critical care practices; phenylephrine is especially useful in counteracting the [[hypotension | hypotensive]] effect of [[epidural]] and [[subarachnoid]] [[anesthetics]]. It also has the advantage of not being [[inotrope | inotropic]] or [[chronotropic]], and so it strictly elevates the blood pressure without increasing the heart rate or contractility (reflex bradycardia may result from the blood pressure increase, however). This is especially useful if the heart is already tachycardic and/or has a [[cardiomyopathy]].
|nonClinToxic=*No long-term animal studies have been done to evaluate the potential of phenylephrine in these areas.
==Side effects==
<!--Clinical Studies-->
The primary side effect of phenylephrine is [[hypertension]]. Patients with congestion and hypertension are typically advised to avoid products containing phenylephrine.
|clinicalStudies=*Increases in systolic and mean blood pressure following administration of phenylephrine were observed in 42 literature-based studies in the perioperative setting, including 26 studies where phenylephrine was used in low-risk (ASA 1 and 2) pregnant women undergoing neuraxial [[anesthesia]] during [[cesarean delivery]], 3 studies in non-obstetric surgery under neuraxial anesthesia, and 13 studies in patients undergoing surgery under [[general anesthesia]]. Mean arterial blood pressure increases were also observed in two double-blind, active-controlled studies in patients with [[septic shock]].
Patients with a history of epilepsy and on anticonvulsant medication should not take this substance. The drug interaction might produce seizures.
<!--How Supplied-->
|howSupplied=*Phenylephrine Hydrochloride Injection, USP, is supplied as follows:
:*NDC 0641-6142-25: 1 mL single dose vials packaged in cartons containing 25 vials per carton.
==Legal issues==
*Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Keep covered in carton until time of use. For single use only. Discard unused portion.
Pseudoephedrine and phenylephrine are both used as decongestants; and until recently, [[pseudoephedrine]] was much more commonly available in the United States. This has changed because provisions of the [[Combat Methamphetamine Epidemic Act of 2005]] placed restrictions on the sale of pseudoephedrine products to prevent the clandestine manufacture of [[methamphetamine]]. Since 2004, phenylephrine has been increasingly marketed as a substitute for pseudoephedrine; some manufacturers have changed the active ingredients of products to avoid the restrictions on sales. <ref name="HeraldTribune"/> Phenylephrine has been off patent for a long time; there are many generic brands available.
==Questions about effectiveness==
<!--Patient Counseling Information-->
Pharmacists Leslie Hendeles and Randy Hatton of the [[University of Florida]] suggested in 2006 that oral phenylephrine is ineffective as a decongestant at the 10 mg dose used, arguing that the studies used for the regulatory approval of the drug in the United States in 1976 were inadequate to prove effectiveness at the 10 mg dose and safety at higher doses.
|fdaPatientInfo=*Inform patients, families, or caregivers that the primary side effect of phenylephrine is [[hypertension]] and rarely, [[hypertensive crisis]]. Patients may experience [[bradycardia]] (slow heart rate), which in some cases may produce heart block or other [[cardiac arrhythmias]], extra ventricular beats, [[myocardial ischemia]] in patients with underlying [[cardiac disease]], and [[pulmonary edema]] (fluid in the lungs) or [[rales]]. Common, less serious symptoms include the following:
<ref name="Hendeles2006">Heldeles, L. and Hatton, R. Oral phenylephrine: An ineffective replacement for pseudoephedrine? ''Journal of Allergy and Clinical Immunology'', Volume 118, Issue 1, Pages 279-280</ref>
Other pharmacists have expressed concerns over phenylephrine's effectiveness as a nasal decongestant
<ref name="UFL"/>
and other clinicians have indicated concern for regulatory actions that reduce the availability of pseudoephedrine.
<ref name=BJMrr>Eccles, R. [http://www.bmj.com/cgi/eletters/332/7538/382-b Phenylephrine an ineffective replacement for pseudoephedrine in response to the methamphetamine problem in the USA]. bmj.com. (May 2006)</ref>
<ref name="BJM">Eccles, R. [http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2125.2006.02833.x Substitution of phenylephrine for pseudoephedrine as a nasal decongestant. An illogical way to control methamphetamine abuse]. ''British Journal of Clinical Pharmacology'' 63. p10. (January 2007)</ref>
A subsequent metaanalysis by the same researchers concluded that there is insufficient evidence for its effectiveness. <ref name="Annals">Hatton, R.C. et al. [http://www.theannals.com/cgi/content/abstract/aph.1H679v1 Efficacy and Safety of Oral Phenylephrine: A Systematic Review and Meta-Analysis] ''Annals of Pharmacotherapy'' (published online Jan 2007)</ref>
The matter is still under debate, though the [[Food and Drug Administration]] has stood by its 1976 approval.
<ref name="HeraldTribune">Hilenmeyer, K. [http://www.heraldtribune.com/apps/pbcs.dll/article?AID=/FP/20070130/HEALTHMATTERS/70129001/1025/NEWS06 All stuffed up] ''Southwest Florida Herald-Tribune'' (30 January 2007)</ref>
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Overview
Phenylephrine (injection) is an alpha-1 adrenergic receptor agonist that is FDA approved for the treatment of hypotension, glaucoma, mydriasis induction, and uveitis. Common adverse reactions include nausea, vomiting, headache, and nervousness.
50 mcg to 250 mcg by intravenous bolus administration. The most frequently reported initial bolus dose is 50 mcg or 100 mcg.
0.5 mcg/kg/min to 1.4 mcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal.
Septic or Other Vasodilatory Shock
No bolus.
0.5 mcg/kg/min to 6 mcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal. Doses above 6 mcg/kg/min do not show significant incremental increase in blood pressure.
Uveitis
Posterior Synechiae: Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be used in patients with uveitis when synechiae are present or may develop. The formation of synechiae may be prevented by the use of this solution and atropine or other cycloplegics to produce wide dilation of the pupil. For recently formed posterior synechiae one drop of Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be applied to the upper surface of the cornea and be repeated as necessary, not to exceed three times. Treatment may be continued the following day, if necessary. Atropine sulfate and the application of hot compresses should also be used if indicated.
Glaucoma
Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be used with miotics in patients with open angle glaucoma. It reduces the difficulties experienced by the patient because of the small field produced by miosis, and still it permits and often supports the effect of the miotic in lowering the intraocular pressure in open angle glaucoma. Hence, there may be marked improvement in visual acuity after using Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% in conjunction with miotic drugs.
Mydriasis Induction
Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be used effectively to increase mydriasis with homatropine hydrobromide, cyclopentolate hydrochloride, tropicamide hydrochloride and atropine sulfate.
One drop of the preferred cycloplegic is placed in each eye, followed in 5 minutes by one drop of Phenylephrine Hydrochloride Ophthalmic Solution, 2.5%. Since adequate cycloplegia is achieved at different time intervals after the instillation of the necessary number of drops, different cycloplegics will require different waiting periods to achieve adequate cycloplegia.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phenylephrine (injection) in adult patients.
Non–Guideline-Supported Use
Hypotension, During anesthesia; Prophylaxis
In women undergoing elective cesarean section with spinal anesthesia, phenylephrine reduced the incidence of hypotension when used with ephedrine as prophylaxis.[1]
1 mg phenylephrine bolus followed by continuous intracavernosal phenylephrine infusion of 2 mg/hour.[4]
Regional anesthesia; Adjunct
Phenylephrine 0.125% to combinations of tetracaine 0.5% plus glucose 7.5% or 0.75%.[5]
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Perioperative Hypotension
0.5 mg to 1 mg per every 25 pounds of body weight SUBQ or IM.
Mydriasis Induction
For a “one application method,” Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% may be combined with one of the preferred rapid acting cycloplegics to produce adequate cycloplegia.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phenylephrine (injection) in pediatric patients.
Non–Guideline-Supported Use
Paroxysmal supraventricular tachycardia
Phenylephrine 200 mcg (in 2 doses of 100 mcg each).[6]
Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension
Because of its pressor effects, phenylephrine hydrochloride can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure.
Extravasation of phenylephrine can cause necrosis or sloughing of tissue.
Pressor Effect with Concomitant Oxytocic Drugs
Oxytocic drugs potentiate the pressor effect of sympathomimetic pressor amines including phenylephrine hydrochloride, with the potential for hemorrhagic stroke.
Allergic Reactions
This product contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Phenylephrine hydrochloride can increase the need for renal replacement therapy in patients with septic shock. Monitor renal function.
Adverse Reactions
Clinical Trials Experience
The following adverse reactions associated with the use of phenylephrine hydrochloride were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
α-adrenergic blocking agents, including phenothiazines (e.g., chlorpromazine) and amiodarone block phenylephrine and are in turn blocked by phenylephrine.
Animal reproduction studies have not been conducted with phenylephrine. It is also not known whether phenylephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenylephrine should be given to a pregnant woman only if clearly needed.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phenylephrine (injection) in women who are pregnant.
Labor and Delivery
If vasopressor drugs are either used to correct hypotension or added to the local anesthetic solution, the obstetrician should be cautioned that some oxytocic drugs may cause severe persistent hypertension and that even a rupture of a cerebral blood vessel may occur during the postpartum period.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when phenylephrine hydrochloride is administered to a nursing woman.
Pediatric Use
To combat hypotension during spinal anesthesia in children, a dose of 0.5 mg to 1 mg per 25 pounds of body weight, administered subcutaneously or intramuscularly, is recommended.
Geriatic Use
There is no FDA guidance on the use of Phenylephrine (injection) with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Phenylephrine (injection) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Phenylephrine (injection) with respect to specific racial populations.
Renal Impairment
In patients with end stage renal disease (ESRD) undergoing hemodialysis, dose-response data indicates increased responsiveness to phenylephrine. Consider using lower doses of phenylephrine hydrochloride in ESRD patients.
Hepatic Impairment
In patients with liver cirrhosis [Child Pugh Class A (n=3), Class B (n=5) and Class C (n=1)], dose-response data indicate decreased responsiveness to phenylephrine. Consider using larger doses than usual in hepatic impaired subjects.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phenylephrine (injection) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Phenylephrine (injection) in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Intravenous
Intramuscular
Subcutaneous
Ophthalmic
Monitoring
There is limited information regarding Monitoring of Phenylephrine (injection) in the drug label.
IV Compatibility
Preparing a 100 mcg/mL Solution of Bolus Intravenous Administration
For bolus intravenous administration, withdraw 10 mg (1 mL of a 10 mg/mL concentration) of phenylephrine injection and dilute with 99 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. This will yield a final concentration of 100 mcg/mL. Withdraw an appropriate dose from the 100 mcg/mL solution prior to bolus intravenous administration.
Preparing a Solution for Continuous Intravenous Infusion
For continuous intravenous infusion, withdraw 10 mg (1 mL of 10 mg/mL concentration) of phenylephrine hydrochloride injection and add to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (providing a final concentration of 20 mcg/mL).
Overdosage
Acute Overdose
Signs and Symptoms
Overdosage may induce ventricular extrasystole and short paroxysms of ventricular tachycardia, a sensation of fullness in the head and tingling of the extremities.
The oral LD50 in the rat is 350 mg/kg, in the mouse 120 mg/kg.
Management
Should an excessive elevation of blood pressure occur, it may be immediately relieved by an α-adrenergic blocking agent (e.g. phentolamine).
Chronic Overdose
There is limited information regarding Chronic Overdose of Phenylephrine (injection) in the drug label.
Phenylephrine hydrochloride produces vasoconstriction that lasts longer than that of epinephrine and ephedrine. Responses are more sustained than those to epinephrine, lasting 20 minutes after intravenous and as long as 50 minutes after subcutaneous injection. Its action on the heart contrasts sharply with that of epinephrine and ephedrine, in that it slows the heart rate and increases the stroke output, producing no disturbance in the rhythm of the pulse.
Phenylephrine is a powerful postsynaptic alpha-receptor stimulant with little effect on the beta receptors of the heart. In therapeutic doses, it produces little if any stimulation of either the spinal cord or cerebrum. A singular advantage of this drug is the fact that repeated injections produce comparable effects.
Structure
Phenylephrine hydrochloride is a vasoconstrictor and pressor drug chemically related to epinephrine and ephedrine. Phenylephrine hydrochloride is a synthetic sympathomimetic agent in sterile form for parenteral injection. Chemically, phenylephrine hydrochloride is (-)-m-Hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrochloride, and has the following structural formula:
Each mL contains: Phenylephrine Hydrochloride 10 mg; Sodium Chloride 3.5 mg; Sodium Citrate Dihydrate 4 mg; Citric Acid Monohydrate 1 mg; Sodium Metabisulfite 2 mg; Water for Injection q.s. pH adjusted with Sodium Hydroxide and/or Hydrochloric Acid if necessary. pH 3.0-6.5.
Pharmacodynamics
The predominant actions of phenylephrine are on the cardiovascular system. Parenteral administration causes a rise in systolic and diastolic pressures in man and other species. Accompanying the pressor response to phenylephrine is a marked reflex bradycardia that can be blocked by atropine; after atropine, large doses of the drug increase the heart rate only slightly. In man, cardiac output is slightly decreased and peripheral resistance is considerably increased. Circulation time is slightly prolonged, and venous pressure is slightly increased; venous constriction is not marked. Most vascular beds are constricted; renal splanchnic, cutaneous and limb blood flows are reduced but coronary blood flow is increased. Pulmonary vessels are constricted, and pulmonary arterial pressure is raised.
The drug is a powerful vasoconstrictor with properties very similar to those of norepinephrine but almost completely lacking the chronotropic and inotropic actions on the heart. Cardiac irregularities are seen only very rarely even with large doses.
Pharmacokinetics
Following an intravenous infusion of phenylephrine hydrochloride, the effective half-life was approximately 5 minutes. The steady-state volume of distribution (340 L) exceeded the body volume by a factor of 5, suggesting a high distribution into certain organ compartments. The average total serum clearance (2095 mL/min) was close to one-third of the cardiac output.
A mass balance study showed that phenylephrine is extensively metabolized by the liver with only 12% of the dose excreted unchanged in the urine. Deamination by monoamino oxidase is the primary metabolic pathway resulting in the formation of the major metabolite (m-hydroxymandelic acid) which accounts for 57% of the total administered dose.
Nonclinical Toxicology
No long-term animal studies have been done to evaluate the potential of phenylephrine in these areas.
Clinical Studies
Increases in systolic and mean blood pressure following administration of phenylephrine were observed in 42 literature-based studies in the perioperative setting, including 26 studies where phenylephrine was used in low-risk (ASA 1 and 2) pregnant women undergoing neuraxial anesthesia during cesarean delivery, 3 studies in non-obstetric surgery under neuraxial anesthesia, and 13 studies in patients undergoing surgery under general anesthesia. Mean arterial blood pressure increases were also observed in two double-blind, active-controlled studies in patients with septic shock.
How Supplied
Phenylephrine Hydrochloride Injection, USP, is supplied as follows:
NDC 0641-6142-25: 1 mL single dose vials packaged in cartons containing 25 vials per carton.
Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Keep covered in carton until time of use. For single use only. Discard unused portion.
Storage
There is limited information regarding Phenylephrine (injection) Storage in the drug label.
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