Phenylephrine (injection)

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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.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- 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.
- 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.
- 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.
- 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.
- 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.

### NonGuideline-Supported Use
- In women undergoing elective cesarean section with spinal anesthesia, phenylephrine reduced the incidence of hypotension when used with ephedrine as prophylaxis.
- 2.5% aqueous or 10% viscous phenylephrine.
- 0.2 to 0.4 mg phenylephrine.
- 1 mg phenylephrine bolus followed by continuous intracavernosal phenylephrine infusion of 2 mg/hour.
- Phenylephrine 0.125% to combinations of tetracaine 0.5% plus glucose 7.5% or 0.75%.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- 0.5 mg to 1 mg per every 25 pounds of body weight SUBQ or IM.
- 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.

### NonGuideline-Supported Use
- Phenylephrine 200 mcg (in 2 doses of 100 mcg each).

# 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

### 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
- 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.
Bradycardia, AV block, ventricular extrasystoles, myocardial ischemia
Nausea, vomiting
Chest pain, edema
Sulfite sensitivity
Headache, nervousness, paresthesia, tremor
Excitability
Pulmonary edema, rales
Diaphoresis, pallor, piloerection, skin blanching, skin necrosis with extravasation
Hypertensive crisis

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Phenylephrine (injection) in the drug label.

# Drug Interactions
- Agonists
- The pressor effect of phenylephrine hydrochloride is increased in patients receiving:
Monoamine oxidase inhibitors (MAOI), such as selegiline.
-adrenergic blockers
-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
- Monoamine oxidase inhibitors (MAOI), such as selegiline.
- -adrenergic blockers
- -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
- -adrenergic blocking agents, including phenothiazines (e.g., chlorpromazine) and amiodarone block phenylephrine and are in turn blocked by phenylephrine.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- 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.
Pregnancy Category (AUS):
- 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 , 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 -adrenergic blocking agent (e.g. phentolamine).

## Chronic Overdose
There is limited information regarding Chronic Overdose of Phenylephrine (injection) in the drug label.

# Pharmacology

## Mechanism of Action
- 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--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 20C to 25C (68F to 77F), excursions permitted to 15C to 30C (59F to 86F). 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.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- 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:
- Chest pain
- Skin or tissue damage if the drug leaks out of the venous catheter into the surrounding tissue
- Headache, nervousness, tremor, numbness/tingling (paresthesias) in hands or feet
- Nausea, vomiting
- Excitability, dizziness, sweating, flushing

# Precautions with Alcohol
- Alcohol-Phenylephrine (injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- PHENYLEPHRINE HYDROCHLORIDE

# Look-Alike Drug Names
There is limited information regarding Phenylephrine (injection) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price