AHFS Class:

• alpha-Adrenergic Agonists 12:12.04

Generic Name(s):

• Phenylephrine Hydrochloride

Phenylephrine hydrochloride is a sympathomimetic amine that predominantly acts by a direct effect on α₁-adrenergic receptors.

Hypotension

Phenylephrine hydrochloride is used parenterally to increase blood pressure and provide hemodynamic support in the management of certain acute hypotensive states.140,141,147,148,149,150,151,153,154,158 Phenylephrine hydrochloride injection is labeled by the US Food and Drug Administration (FDA) for use in the setting of anesthesia or septic shock to treat clinically important hypotension resulting principally from vasodilation.140,141 Evidence supporting the use of IV phenylephrine is based on studies from the published literature, the majority of which were conducted in the perioperative setting.140,141,143,144 Only a few clinical studies have evaluated use of the drug in patients with septic shock.141,144,154,156 The available data clearly indicate that phenylephrine is effective in increasing and maintaining blood pressure in hypotensive patients.140,141,142,143,144,154 In patients who require vasopressor support, individual hemodynamic abnormalities must be identified and monitored so that therapy can be adjusted as necessary. If severe peripheral vasoconstriction exists, phenylephrine may be ineffective and have a deleterious effect by causing further reductions in plasma volume and blood flow to vital organs.

Hypotension During Anesthesia

Phenylephrine hydrochloride is used for the treatment of hypotension during anesthesia.140,141,144,147,149,150,151 Studies performed in a variety of surgical settings have demonstrated that phenylephrine increases systolic and mean arterial blood pressures when administered IV (as a direct “bolus” injection or continuous infusion) following the development of hypotension in patients receiving neuraxial and/or general anesthesia.140,141,142,144 In many of these studies, the drug was used in low-risk pregnant women undergoing cesarean section with neuraxial anesthesia.140,141,144,147,149 Although ephedrine historically has been considered the vasopressor of choice for treatment of hypotension in obstetric anesthesia, phenylephrine is increasingly being used in this setting because of evidence suggesting that the drug may provide a more favorable fetal acid-base balance.147,148,149,150,151

Phenylephrine also has been used for the prevention of hypotension in patients undergoing spinal anesthesia.147,150 However, routine prophylactic use of vasopressors has been questioned because hypotension does not always occur during spinal anesthesia and treatment can readily be instituted if necessary; some clinicians have suggested that vasopressors be administered prophylactically only in those cases in which a substantial decrease in blood pressure is expected.

Septic Shock

Vasopressors are used in the management of vasodilatory shock, the most common form of which is septic shock, to restore blood pressure and tissue perfusion after initial fluid resuscitation is attempted.153,154,158 The Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock recommend norepinephrine as the first-line vasopressor of choice in adults with septic shock; if adequate blood pressure is not achieved, vasopressin or epinephrine may be added.153,154,155,158 Phenylephrine generally has been considered only in selected situations when norepinephrine cannot be used (e.g., because of tachyarrhythmias) or as salvage therapy when other treatment methods have failed.146,154,158 Although data are limited, studies have shown that phenylephrine increases mean arterial pressure in patients with septic shock; however, the regional hemodynamic effects of the drug (particularly in regards to renal blood flow and possible renal toxicity) have not been completely elucidated.141,144,146,154,156,158 (See Cautions: Adverse Effects.) Because of uncertainty regarding the clinical outcomes of phenylephrine therapy, experts currently state that use of the drug should be limited until more information is available.153

Although vasopressors have been used in the management of other types of shock or shock-like states (e.g., hemorrhagic or cardiogenic shock),157,158,159,160 there is insufficient evidence to support the use of phenylephrine for blood pressure support in general shock settings, particularly those not associated with a vasodilatory component.143,144,158 If a vasopressor is required in these situations, norepinephrine usually is preferred.157,158,159

Prolongation of Spinal Anesthesia

Phenylephrine has been used as an additive to solutions of some local anesthetics to decrease the rate of vascular absorption of the anesthetic and prolong the duration of anesthesia†. The risk of systemic toxicity due to the local anesthetic is also decreased. (See Local Anesthetics, Parenteral, General Statement 72:00.) Phenylephrine is not as effective as epinephrine in prolonging local anesthesia but may be preferred when cardiostimulation is undesirable.

Nasal Congestion

Phenylephrine hydrochloride is administered orally for self-medication as a nasal decongestant for temporary relief of nasal congestion associated with upper respiratory allergy (e.g., hay fever) or the common cold; the drug also is used to provide temporary relief of sinus congestion and pressure.114 Preparations containing phenylephrine in fixed combination with other agents (e.g., acetaminophen, chlorpheniramine, dextromethorphan, diphenhydramine, guaifenesin, pheniramine) are used 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 state and federal actions restricting the sale and purchase of nonprescription preparations containing decongestants such as pseudoephedrine, ephedrine, or phenylpropanolamine (no longer commercially available in the US),109,110,111,112 some manufacturers reformulated various nonprescription pseudoephedrine-containing preparations by substituting phenylephrine for pseudoephedrine.113,116 (See Uses: Misuse and Abuse, in Pseudoephedrine 12:12.12.) However, few studies evaluating the efficacy of oral phenylephrine in the treatment of nasal congestion have been published, and efficacy of the drug at currently recommended oral dosages has been questioned by some clinicians.115,125,126,127

Nasal decongestants, including phenylephrine, have been used for self-medication for the temporary relief of nasal congestion associated with sinusitis.114,117 However, prospective studies of nasal decongestants for this use are lacking,118 and data on their use as adjunctive therapy in the management of sinusitis are limited and controversial.117,119 Furthermore, evidence from an animal study indicated that topical nasal decongestants (i.e., oxymetazoline) may increase the degree of sinus inflammation,120 potentially delaying resolution of sinusitis.117 Because labeling for nonprescription (over-the-counter, OTC) nasal decongestant preparations previously included use for sinusitis, there were concerns that consumers would assume that nasal decongestants were effective in the treatment of sinusitis, thereby choosing self-medication over medical evaluation and definitive treatment by a clinician; such delay in medical evaluation could result in a lost opportunity for early diagnosis of another serious medical condition (e.g., bacterial sinusitis).117 The FDA no longer considers oral or topical nasal decongestants appropriate for self-medication of sinusitis.117 In October 2005, the agency issued a final rule, which was effective in 2007, that amended the final monograph for OTC nasal decongestant preparations to remove the indication for relief of nasal congestion associated with sinusitis from labeling and prohibited use of the term “sinusitis” elsewhere in labeling.117

Phenylephrine also is applied topically to the nasal mucosa as a vasoconstrictor to relieve nasal congestion. (See Phenylephrine 52:32.)

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 Vasoconstrictors also 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 Phenylephrine also may relieve pruritus associated with histamine release.102,108 However, vasoconstrictors are expected to provide only partial relief of pruritus associated with hemorrhoids, and there are more effective agents for relief of anorectal itching.108 The presence of other ingredients in the formulation (e.g., protectants, local anesthetics, astringents, antipruritics, analgesics) may provide additional relief of these and other anorectal symptoms (e.g., discomfort, pain, burning) associated with hemorrhoids.101,102,103,104,105,106,107 Although locally applied vasoconstrictors have been shown to alter mucosal blood flow, safety and efficacy for self-medication control of minor hemorrhoidal bleeding have not been established.102,108 If minor bleeding is present, a clinician should be consulted promptly for advice because anorectal bleeding may be a sign of conditions ranging in seriousness from simple abrasions to cancer.108

Effectiveness of topical or intrarectal therapy with phenylephrine for relief of symptoms secondary to swollen hemorrhoidal tissues is based on a predicted effect of the drug's vasoconstrictive activity in reducing capillary and arteriovenous congestion in the anorectal area rather than on specific efficacy studies.108 Effective dosage of anorectal therapy with the drug was based on predictions from established efficacy of local therapy for nasal congestion.108

Other Uses

For the use of phenylephrine as a mydriatic, see Phenylephrine Hydrochloride 52:24. For the use of phenylephrine as a vasoconstrictor in the eye or mucosa, see Phenylephrine Hydrochloride 52:32.

Administration

Parenteral Administration

Phenylephrine hydrochloride injection concentrate is administered after dilution by direct IV (“bolus”) injection or continuous IV infusion.140,141 The drug also has been administered by IM† or subcutaneous injection†. The route of administration should be determined by the specific clinical situation and needs of the individual patient. For treatment of hypotension during anesthesia, the manufacturers recommend administration of phenylephrine hydrochloride as an IV injection or continuous infusion; when used in the treatment of septic shock, the drug should be administered as a continuous IV infusion with no initial bolus dose.140,141

Commercially available phenylephrine hydrochloride injection concentrate must be diluted with a compatible IV solution prior to administration as a direct IV (“bolus”) injection or continuous infusion.140,141 To prepare solutions for direct IV injection, 1 mL of the commercially available phenylephrine hydrochloride injection containing 10 mg/mL should be withdrawn and diluted with 99 mL of 5% dextrose or 0.9% sodium chloride injection to provide a final concentration of 100 mcg/mL.140,141 To prepare solutions for continuous IV infusion, 1 mL of the commercially available phenylephrine hydrochloride injection containing 10 mg/mL should be withdrawn and added to 500 mL of 5% dextrose or 0.9% sodium chloride injection to provide a final concentration of 20 mcg/mL.140,141 Diluted solutions may be stored at room temperature for up to 4 hours or under refrigeration for up to 24 hours; any unused portions should be discarded.140,141

Commercially available phenylephrine hydrochloride bulk vials are intended for use in a pharmacy admixture program for preparation of single doses to be dispensed to multiple patients.140 Each vial should be penetrated only one time with a suitable sterile transfer device or dispensing set.140 The pharmacy bulk vial should be discarded within 4 hours after initial entry.140

Prior to administration, phenylephrine hydrochloride solutions should be inspected visually for particulate matter and discoloration; the drug should be discarded if the solution is colored, cloudy, or contains any particulate matter.140,141

During IV administration of phenylephrine, intravascular volume depletion and acidosis should always be corrected if present.140,141 Blood pressure should be monitored and dosage of phenylephrine hydrochloride adjusted as necessary to achieve appropriate blood pressure goals.140,141 Care should be taken to avoid extravasation and the infusion site should be checked for free flow.140

Standardize 4 Safety

Standardized concentrations for phenylephrine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249,250Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249,250Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249,250 For additional information on S4S (including updates that may be available), see [Web].249,250

Oral Administration

As a vasoconstrictor for the management of nasal congestion, phenylephrine is administered orally alone or as a fixed-combination decongestant preparation.

Topical and Rectal Administration

As a vasoconstrictor for the management of hemorrhoidal symptoms, phenylephrine hydrochloride 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

Topical preparations of phenylephrine hydrochloride that are labeled for external use only should be applied externally to the affected area and should not be administered inside the rectum by either using fingers or any mechanical device or applicator.101,102,103,105,107

Rectal preparations of phenylephrine hydrochloride 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, 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 the applicator should be cleansed thoroughly after each use and stored according to the manufacturer's instructions.104 Such preparations should not be used if introduction of the applicator or device into the rectum causes additional pain; patients should be advised to consult a clinician promptly in such cases.101,102,104,107 The wrapper should be removed from suppositories prior to insertion into the rectum.101,102,106,107

Patients receiving phenylephrine hydrochloride for the local management of hemorrhoids should be advised 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 The area then should be dried by patting or blotting with toilet tissue or a soft cloth before application of the drug.101,102,103,104,105,106,107

Dosage

Phenylephrine hydrochloride should be administered in the lowest effective dosage for the shortest possible time. When used to increase blood pressure in patients with acute hypotensive states, dosage should be individualized based on the pressor response.

Hypotension During Anesthesia

Various phenylephrine hydrochloride dosing regimens have been used for the treatment of hypotension during anesthesia; optimal dosage and method of administration remain to be established.140,141,145,147,148,160,161 Dosages currently recommended by the manufacturers are based on information from published studies.140,141,142,144

For the treatment of hypotension during anesthesia in adults, the manufacturers recommend direct IV (“bolus”) doses of phenylephrine hydrochloride ranging from 40-250 mcg; the usual initial dose is 50 or 100 mcg.140,141 One manufacturer states that additional IV bolus doses may be administered every 1-2 minutes as needed not to exceed a total dosage of 200 mcg; however, if blood pressure is below the target goal, a continuous IV infusion should be initiated.140 If phenylephrine hydrochloride is administered by continuous IV infusion, the manufacturers recommend infusion rates of 10-35 mcg/minute or 0.5-1.4 mcg/kg per minute.140,141 The infusion generally should be started at a low rate and titrated to effect.142 Other dosage regimens for phenylephrine hydrochloride have been recommended for the treatment of hypotension;160,161 in all situations, dosage should be titrated to effect and the patient should be closely monitored.140,141,160,161

Some manufacturers state that total dosage of phenylephrine hydrochloride should not exceed 200 mcg (if given by direct IV injection) or 200 mcg/minute (if given by continuous IV infusion).140 Higher dosages do not necessarily produce incremental increases in blood pressure and may cause hypertension and reflex bradycardia.140,142,148

Septic Shock

When used in the treatment of septic shock, phenylephrine hydrochloride is administered by continuous IV infusion without an initial bolus dose.141 (See Dosage and Administration: Administration.) For the treatment of septic shock or other vasodilatory shock in adults, the manufacturer recommends that phenylephrine hydrochloride therapy be initiated at an infusion rate of 0.5-6 mcg/kg per minute; the rate of infusion should be adjusted to maintain the target blood pressure goal.141 Infusion rates higher than 6 mcg/kg per minute do not appear to provide substantial incremental increases in blood pressure.141,144

Prolongation of Spinal Anesthesia

To prolong spinal anesthesia†, 2-5 mg of phenylephrine hydrochloride has been added to the anesthetic solution, and has increased the duration of nerve block by as much as approximately 50%.160

Vasoconstriction for Regional Anesthesia

To produce vasoconstriction in regional anesthesia†, some clinicians state that the optimum concentration of phenylephrine hydrochloride is 0.05 mg/mL (1:20,000). Solutions have been prepared for regional anesthesia by adding 1 mg of phenylephrine hydrochloride to each 20 mL of local anesthetic solution. Some pressor response can be expected when at least 2 mg is injected.

Nasal Congestion

Phenylephrine is administered orally as a nasal decongestant alone or in fixed combination with other drugs.133,134,135,136,137,138,139 The usual oral decongestant dosage of phenylephrine hydrochloride for self-medication in adults and children 12 years of age or older is 10 mg every 4 hours.114 The manufacturer states that no more than 6 doses should be administered in a 24-hour period.114 For self-medication , the manufacturer recommends that patients discontinue the drug and consult a clinician if symptoms persist more than 7 days or are accompanied by fever, or if nervousness, dizziness, or insomnia occurs.114

Hemorrhoids

When used topically or rectally as a vasoconstrictor for temporary relief of hemorrhoidal symptoms in adults and children 12 years of age and older, phenylephrine hydrochloride is used for 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 Anorectal preparations of the drug usually are administered 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

Patients should be advised not to exceed the recommended dosage of phenylephrine hydrochloride unless otherwise directed by a clinician.101,102,103,104,105,106,107 108 Although the systemic bioavailability of phenylephrine hydrochloride following local application to the anorectal area is not known, it is recommended that anorectal dosage for self-medication of hemorrhoids not exceed 2 mg daily (i.e., 0.5 mg 4 times daily) in order to minimize adverse systemic effects.108 It currently is not known whether higher dosages would provide additional benefit.108

Patients should be advised 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

Adverse Effects

Systemic Use

Phenylephrine hydrochloride may cause restlessness, anxiety, nervousness, weakness, dizziness, precordial pain or discomfort, tremor, respiratory distress, pallor or blanching of the skin, or a pilomotor response. Injections of the drug may be followed by paresthesia in the extremities or a feeling of coolness in the skin. When 2 mg or more of phenylephrine hydrochloride is injected during regional local anesthesia, a pressor response may occur.

Overdosage of phenylephrine may cause a rapid rise in blood pressure and associated manifestations including headache, seizures, cerebral hemorrhage, palpitation, paresthesia, and vomiting. Hypertensive crisis also has been reported.140,141 Hypertension may be relieved by administration of an α-adrenergic blocking agent (e.g., phentolamine).

Phenylephrine can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion, and possibly reduced urine output and metabolic acidosis. In patients with septic shock, phenylephrine may increase the need for renal replacement therapy.140,141 Severe vasoconstrictive effects may be more likely to occur in patients with substantial peripheral vascular disease.140,141 In addition, prolonged use of phenylephrine may cause plasma volume depletion that may result in perpetuation or recurrence of hypotension when the drug is discontinued.

Phenylephrine can cause severe bradycardia and decreased cardiac output.140,141 Decreased cardiac output may be especially harmful to elderly patients and/or those with initially poor cerebral or coronary circulation. Bradycardia may be treated by administration of atropine. Because of its potent vasoconstricting effects, phenylephrine may precipitate angina in patients with a history of the condition or with severe atherosclerosis.140,141 The drug also increases cardiac work by increasing peripheral arterial resistance and may possibly induce or exacerbate heart failure. In addition, phenylephrine may increase pulmonary arterial pressure. In patients with autonomic dysfunction (e.g., those with spinal cord injuries), the blood pressure response to phenylephrine may be increased.140,141

Phenylephrine may cause necrosis or sloughing of tissue if extravasation occurs during IV administration or following subcutaneous administration.

Anorectal Use

When used in recommended dosages for local effect in anorectal disorders (e.g., hemorrhoids), adverse systemic effects of vasoconstrictors such as phenylephrine generally are minimal.108 Such effects, although unlikely, can include blood pressure elevation, cardiac arrhythmia or irregular heart rate, CNS disturbance or nervousness, tremor, sleeplessness, and aggravation of hyperthyroid symptoms.108

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

Phenylephrine reportedly is less likely than other topical vasoconstrictors (e.g., ephedrine, epinephrine) to cause local irritation.108 Contact dermatitis has been reported following topical application of certain formulations of vasoconstrictors.108

The possibility that topical anorectal application of vasoconstrictors if absorbed systemically in adequate amounts could interact with monoamine oxidase (MAO) inhibitors resulting in potentiated hypertensive effects should be considered.108 Such hypertensive potentiation could result in serious, potentially fatal effects such as cerebral hemorrhage or stroke.108 (See Anorectal Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Precautions and Contraindications

Vasopressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes. Blood volume depletion should be corrected as fully as possible before or during administration with phenylephrine hydrochloride. In an emergency, the drug may be used 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. Hypoxia and acidosis, which also may reduce the effectiveness of phenylephrine, must be identified and corrected prior to or concurrently with administration of the drug.

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. Because phenylephrine can cause necrosis of the skin and subcutaneous tissue, care should be taken to avoid extravasation of the drug during IV administration and the infusion site should be checked for free flow.140

As with other sympathomimetic drugs, phenylephrine hydrochloride should not be used for self-medication of nasal congestion in patients with thyroid disease, diabetes mellitus, hypertension, or heart disease without consulting a clinician.114 In addition, the drug should not be used for self-medication of nasal congestion in patients with difficulty urinating because of prostatic hypertrophy without consulting a clinician.114 Patients should be advised to discontinue the drug and consult a clinician if symptoms persist more than 7 days or are accompanied by fever, or if nervousness, dizziness, or insomnia develops during therapy.114 In addition, patients should be advised to avoid phenylephrine if they are currently receiving or have recently received (i.e., within 2 weeks) an MAO inhibitor.114

When phenylephrine is used in combination with other drugs, the cautions applicable to all ingredients in the formulations should be kept in mind.133,134,135,136,137,138,139

Commercially available formulations of phenylephrine hydrochloride injection may contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.140,141 The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals. Some manufacturers state that phenylephrine is contraindicated in patients with hypersensitivity to the drug or any of its components.141

Some clinicians consider severe coronary disease or cardiovascular disease (including myocardial infarction) to be contraindications to use of phenylephrine. Because of possible renal toxicity in patients with septic shock, renal function should be monitored during phenylephrine use in such patients.140,141

Anorectal Precautions and Contraindications

Unless otherwise directed by a clinician, patients should not receive external or rectal preparations of vasoconstrictors such as phenylephrine hydrochloride for self-medication of hemorrhoidal symptoms if they have cardiac disease, high blood pressure, thyroid disease, diabetes mellitus, or difficulty in urination secondary to prostatic hyperplasia.101,102,103,104,105,106,107,108 Patients also should be advised to 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 For additional precautions associated with anorectal phenylephrine therapy, see Dosage and Administration.

Pediatric Precautions

The manufacturers state that safety and efficacy of parenteral preparations of phenylephrine hydrochloride have not been established in pediatric patients;140,141 however, the drug has been used in children for the treatment of hypotension during spinal anesthesia.160

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, 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 There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by the US Food and Drug Administration [FDA]) have not been established.128 Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of a the agency continues to assess safety and efficacy of these preparations in older children. Meanwhile, 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 agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age. FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in Pseudoephedrine 12:12.12.

Geriatric Precautions

Clinical studies of phenylephrine hydrochloride did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.140,141 Clinical experience to date has not identified any differences in response between geriatric and younger patients.140,141 If phenylephrine is used in geriatric patients, dosage should be selected carefully, usually starting at the low end of the dosage range, since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group.140,141

Pregnancy and Lactation

Pregnancy

It is not known whether phenylephrine hydrochloride can cause fetal harm when administered to pregnant women; the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.140,141 Animal studies suggest a potential for adverse cardiovascular effects to the fetus if the drug is administered IV during pregnancy.140 Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia and bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.132

In studies of IV phenylephrine in pregnant women undergoing cesarean delivery with neuraxial anesthesia, common adverse effects reported in the mother included nausea and vomiting, bradycardia, reactive hypertension, and transient arrhythmias.140,141 The drug did not appear to affect neonatal Apgar scores or umbilical artery blood-gas status.140,141

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

Lactation

It is not known whether phenylephrine is distributed into human milk following parenteral administration.140,141 The drug should be used with caution in nursing women.140

- and Beta-Adrenergic Blocking Agents

The effects of both phenylephrine and α-adrenergic blocking agents may be blocked when these drugs are administered concomitantly.140,141 The vasopressor response to phenylephrine is decreased by prior administration of an α-adrenergic blocking agent such as phentolamine mesylate. Phenothiazine drugs (e.g., chlorpromazine) and amiodarone also have some α-adrenergic blocking effects and can reduce the pressor effect of phenylephrine.141

The pressor effects of phenylephrine may be increased with concomitant administration of β-adrenergic blocking drugs.141

Oxytocic Drugs

When a vasopressor (e.g., phenylephrine) is used in conjunction with oxytocic drugs, the pressor effect is potentiated, increasing the risk of hemorrhagic stroke.132,140,141 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 period.132

General Anesthetics

Rarely, administration of phenylephrine to patients who have received cyclopropane or halogenated hydrocarbon general anesthetics that increase cardiac irritability and seem to sensitize the myocardium to phenylephrine may result in arrhythmias. However, in usual therapeutic doses, phenylephrine is much less likely to produce arrhythmias than is norepinephrine or metaraminol.

Monoamine Oxidase Inhibitors

The cardiac and pressor effects of phenylephrine are potentiated by prior administration of monoamine oxidase (MAO) inhibitors (e.g., selegiline) because the metabolism of phenylephrine is reduced. 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 drug. Oral administration of phenylephrine to patients receiving a MAO inhibitor should be avoided. Parenteral administration of phenylephrine to these patients, if unavoidable, should be undertaken with extreme caution and with low initial doses. Patients should consult a clinician before initiating anorectal phenylephrine therapy if they are receiving an MAO inhibitor. (See Anorectal Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Other Drugs

Other drugs that may potentiate the pressor effect of phenylephrine include α₂-adrenergic agonists (e.g., clonidine), tricyclic antidepressants, atropine sulfate, steroids, norepinephrine-reuptake inhibitors (e.g., atomoxetine), and ergot alkaloids (e.g., methylergonovine maleate).140,141 Other drugs that can antagonize the pressor effect of phenylephrine include phosphodiesterase (PDE) type 5 inhibitors, benzodiazepines, and antihypertensive agents.140

Atropine sulfate blocks the reflex bradycardia caused by phenylephrine and enhances the pressor response to phenylephrine.

An excessive rise in blood pressure may occur if phenylephrine is administered to patients receiving a parenteral injection of an ergot alkaloid such as ergonovine maleate.132

The possibility that digitalis can sensitize the myocardium to the effects of sympathomimetic drugs should be considered.

Administration of furosemide or other diuretics may decrease arterial responsiveness to vasopressors such as phenylephrine.

Pharmacology

Phenylephrine acts predominantly by a direct effect on α₁-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. Phenylephrine does not stimulate β-adrenergic receptors of the bronchi or peripheral blood vessels (β₂-adrenergic receptors). Phenylephrine also has an indirect effect by releasing norepinephrine from its storage sites. The main effect of phenylephrine at therapeutic doses is vasoconstriction.

Cardiovascular Effects

Phenylephrine constricts both arterial and venous blood vessels, although its effects on arterial vessels are more pronounced.152 Systemic vascular resistance is increased, resulting in increased systolic blood pressure, diastolic blood pressure, and mean arterial pressure. Vasoconstriction occurs in most vascular beds, including renal, pulmonary, and splanchnic arteries, but minimal to no effect is observed on cerebral blood vessels.140,141,152 In some patients, phenylephrine can substantially reduce cardiac output, presumably due to increased afterload; however, the exact effects of the drug on global cardiac output depend on the dose and contributory effects of the arterial and venous vasculature.152 Although phenylephrine reduces venous compliance and can potentially increase venous return, accompanying increases in arterial and venous resistance can negate this potential benefit.152 Phenylephrine may reduce circulating plasma volume (especially with prolonged use) as a result of loss of fluid into the extracellular spaces caused by postcapillary vasoconstriction. In contrast to methoxamine, phenylephrine constricts coronary and pulmonary blood vessels. Pulmonary arterial pressure usually is increased; however, a decrease in pulmonary arterial pressure has occurred in some patients, probably because of decreased cardiac output secondary to reflex bradycardia. At clinically relevant doses, phenylephrine increases myocardial work and oxygen requirements.152

Constriction of renal blood vessels by phenylephrine may decrease renal blood flow. In hypotensive patients, phenylephrine may initially decrease urine flow and excretion of sodium and potassium. If the patient is not hypovolemic, renal blood flow and glomerular filtration rate increase as the systemic blood pressure is raised toward normal levels; however, renal blood flow and glomerular filtration rate again decrease if blood pressure is further increased toward hypertensive levels.

Phenylephrine can cause reflex bradycardia because of increased vagal activity.140,141 In some patients, phenylephrine has caused a paradoxical increase in heart rate when administered to treat hypotension occurring after spinal anesthesia. Because of some β₁-adrenergic activity, phenylephrine can exert positive inotropic effects on the myocardium at doses greater than those usually used therapeutically.152 Rarely, the drug may increase myocardial excitability, causing arrhythmias such as atrioventricular nodal rhythm, premature ventricular beats, ventricular tachycardia, or ventricular extrasystoles.

Local vasoconstriction and hemostasis also occur following topical application or infiltration of phenylephrine into tissues. Like epinephrine, phenylephrine probably produces hemostasis in cases of small vessel bleeding but does not control bleeding from larger vessels. Following oral administration or topical application of phenylephrine to the mucosa, constriction of blood vessels in the nasal mucosa may relieve nasal congestion.

Other Effects

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

As a result of its effects on α-adrenergic receptors, phenylephrine 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 blood pressure.

Pharmacokinetics

Absorption

Phenylephrine is completely absorbed following oral administration and undergoes extensive first-pass metabolism in the intestinal wall.121,122 The bioavailability of phenylephrine following oral administration is approximately 38% relative to IV administration.121,122 Because of extensive first-pass metabolism, there is considerable interindividual and possibly intraindividual variation in oral bioavailability of the drug.121 Following oral administration of phenylephrine (1 or 7.8 mg), peak serum concentrations occur at 0.75-2 hours.121,122

To achieve cardiovascular effects, phenylephrine should be given parenterally. After IV administration, a pressor effect occurs almost immediately and persists for 15-20 minutes. After IM administration, a pressor effect occurs within 10-15 minutes and persists for 30 minutes to 1 or 2 hours. Occasionally, enough phenylephrine may be absorbed after oral inhalation to produce systemic effects. Following oral administration, nasal decongestion may occur within 15 or 20 minutes and may persist for 2-4 hours.

Distribution

Phenylephrine undergoes rapid distribution into peripheral tissues; there is some evidence that the drug may be stored in certain organ compartments.121 The pharmacologic effects of phenylephrine are terminated at least partially by uptake of the drug into tissues. Penetration of phenylephrine into the brain appears to be minimal.121

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

Elimination

Phenylephrine undergoes extensive metabolism in the intestinal wall (first-pass) and in the liver.121,122 The principal routes of metabolism involve sulfate conjugation (primarily in the intestinal wall) and oxidative deamination (by monoamine oxidase [MAO]); glucuronidation also occurs to a lesser extent.121,122 The metabolites are not pharmacologically active.140

Phenylephrine and its metabolites are excreted mainly in urine.121,122 Following oral or IV administration, approximately 80 or 86% of the dose, respectively, is excreted in urine within 48 hours, principally as metabolites; approximately 2.6% of an oral dose or 16% of an IV dose is excreted in urine as unchanged drug.121,122 The terminal elimination half-life of phenylephrine averages 2-3 hours following oral or IV administration.121,122 The observed effective half-life is approximately 5 minutes following IV infusion of the drug.140

Clinical data regarding effects of renal or hepatic impairment on the pharmacokinetics of phenylephrine are limited.121 Because the majority of an oral dose is metabolized in the intestinal wall and a lower fraction in the liver, hepatic impairment is unlikely to result in major changes following oral administration; however, phenylephrine pharmacokinetics may be substantially altered following IV administration of the drug.121 Patients with hepatic cirrhosis may have a reduced response to phenylephrine, potentially requiring higher dosages of the drug.140,141,142 Patients with end-stage renal disease may have an increased response to phenylephrine, potentially requiring lower dosages of the drug.140,141,142,144

Chemistry and Stability

Chemistry

Phenylephrine is a sympathomimetic amine that is pharmacologically similar to methoxamine hydrochloride. Phenylephrine is commercially available as the hydrochloride. Commercially available phenylephrine hydrochloride injections may contain the antioxidant, sodium metabisulfite.140,141

Stability

Phenylephrine hydrochloride injection should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C; single-dose and pharmacy bulk vials should be kept in their original carton until time of use and protected from light.140,141

Phenylephrine hydrochloride oral tablets should be stored at 15-25°C in a dry place.114 Phenylephrine hydrochloride injections should be stored at room temperature up to 30°C and protected from light.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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. [Web]

104. Wyeth. Preparation H^® (ointment) prescribing information. From Wyeth website. 2003. [Web]

105. Wyeth. Preparation H^® (gel) prescribing information. From Wyeth website. 2003. [Web]

106. Wyeth. Preparation H^® (suppositories) prescribing information. From Wyeth website. 2003. [Web]

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. [Web]

110. National Alliance for Model State Drug Laws. Methamphetamine Information. From the Alliance website. Accessed October 3, 2005. [Web]

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. [Web]

112. Anon. Senate approves anti-meth bill. CBS News, 2005 Sep 10. From CBS news website. [Web]

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. [Web]

115. Hendeles L. Selecting a decongestant. Pharmacotherapy . 1993; 13:129S-134S. [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.

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]

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 from website. Accessed 2006 Sep 7. [Web]

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. [Web]

130. Anon. Makers pull cold medicines sold for infants. CNN News, 2007 Oct 11. From CNN.com website. [Web]

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. [Web]

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. [Web]

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. [Web]

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

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. [Web]

138. McNeil-PPC, 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. [Web]

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. [Web]

140. Eclat Pharmaceuticals. Vazculep^® (phenylephrine hydrochloride injection) prescribing information. Chesterfield, MO; 2014 July.

141. West-Ward Pharmaceuticals. Phenylephrine hydrochloride injection prescribing information. Eatontown, NJ; 2014 June.

142. Food and Drug Administration. Summary review for regulatory action: NDA#204300/S-000. From FDA website. [Web]

143. Food and Drug Administration. Summary review for regulatory action: NDA#203826/S-000. From FDA website. [Web]

144. Food and Drug Administration. Medical review for regulatory action: NDA#203826/S-000. From FDA website. [Web]

145. Palanisamy A. What's new in Obstetric Anesthesia? The 2013 Gerard W. Ostheimer lecture. Anesth Analg . 2014; 118:360-6. [PubMed 24445636]

146. Thiele RH, Nemergut EC, Lynch C. The clinical implications of isolated alpha(1) adrenergic stimulation. Anesth Analg . 2011; 113:297-304. [PubMed 21519053]

147. Habib AS. A review of the impact of phenylephrine administration on maternal hemodynamics and maternal and neonatal outcomes in women undergoing cesarean delivery under spinal anesthesia. Anesth Analg . 2012; 114:377-90. [PubMed 22104076]

148. Ngan Kee WD. Phenylephrine infusions for maintaining blood pressure during spinal anesthesia for cesarean delivery: finding the shoe that fits. Anesth Analg . 2014; 118:496-8. [PubMed 24557093]

149. Ngan Kee WD, Khaw KS, Tan PE et al. Placental transfer and fetal metabolic effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology . 2009; 111:506-12. [PubMed 19672175]

150. Nag DS, Samaddar DP, Chatterjee A et al. Vasopressors in obstetric anesthesia: A current perspective. World J Clin Cases . 2015; 3:58-64. [PubMed 25610851]

151. American Society of Anesthesiologists Task Force on Obstetric Anesthesia. Practice guidelines for obstetric anesthesia: an updated report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia. Anesthesiology . 2007; 106:843-63. [PubMed 17413923]

152. Thiele RH, Nemergut EC, Lynch C. The physiologic implications of isolated alpha(1) adrenergic stimulation. Anesth Analg . 2011; 113:284-96. [PubMed 21519050]

153. Rhodes A, Evans LE, Alhazzani W et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med . 2017; 43:304-377. [PubMed 28101605]

154. Hollenberg SM, Ahrens TS, Annane D et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med . 2004; 32:1928-48. [PubMed 15343024]

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

156. Morelli A, Ertmer C, Rehberg S et al. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial. Crit Care . 2008; 12:R143.

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

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

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

160. Sandoz. Phenylephrine hydrochloride injection prescribing information. Princeton, NJ; 2010 May.

161. Flerlage J, Engorn B, eds. The Harriet Lane handbook: a manual for pediatric house officers. 20th ed. Philadelphia, PA: Saunders; 2015:872-3.

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

249. ASHP. Standardize 4 Safety: pediatric continuous infusion standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]

250. ASHP. Standardize 4 Safety: adult continuous infusion standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]

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.