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Home > AHFS Drug Information > Autonomic Drugs 12:00 > Sympathomimetic (Adrenergic) Agents 12:12 > α-Adrenergic Agonists 12:12.04 Phenylephrine Hydrochloride Sub-sections Introduction Uses Dosage and Administration Cautions Drug Interactions Pharmacology Pharmacokinetics Chemistry and Stability Preparations References Drug Nomenclature Generic Name: Phenylephrine Hydrochloride CAS Number: 61-76-7 Introduction Phenylephrine is a sympathomimetic amine that predominantly acts by a direct effect on α-adrenergic receptors. Uses Hypotension and Shock Phenylephrine is administered parenterally to produce vasoconstriction as an adjunct to correct hemodynamic imbalances in the treatment of shock that persists after adequate fluid volume replacement. (See Cautions: Precautions and Contraindications.) Individual hemodynamic abnormalities must be identified and monitored so that therapy can be adjusted as necessary. If severe peripheral vasoconstriction exists, the drug may be ineffective and may have a deleterious effect by causing further reductions in plasma volume and blood flow to vital organs. The value of pressor therapy in shock, especially when caused by septicemia, burns, trauma, or drug overdosage, is questionable, either because the effectiveness has not been proved or because vasoconstriction caused by the drug may adversely affect the patient. Although a vasopressor may be indicated if the patient fails to respond to administration of fluids, a change in position or other measures directed to the specific cause of shock, drugs that also stimulate the myocardium (e.g., norepinephrine, metaraminol) usually are preferred to phenylephrine, especially in shock caused by myocardial infarction, septicemia, or surgical complications. Some clinicians believe that phenylephrine should not be used in the management of shock, especially when caused by myocardial infarction, because it greatly increases arterial resistance and the workload on the heart. However, phenylephrine may be useful when cardiac stimulation is undesirable (as in the treatment of hypotension occurring during general anesthesia with cyclopropane, halothane, or other agents that sensitize the myocardium to arrhythmias). Vasopressor therapy in overdosage of barbiturates or other sedatives is especially controversial; some clinicians have stated that the incidence of mortality actually may be increased when a vasopressor is given. The manufacturer states that phenylephrine may be used to treat hypotension or shock resulting from overdosage of or idiosyncratic reactions to certain drugs (e.g., adrenergic and ganglionic blocking agents, rauwolfia and veratrum alkaloids, phenothiazines). Although the manufacturer states phenylephrine may be useful to control shock following pheochromocytomectomy, shock generally can be prevented by maintenance of adequate blood volume and/or preoperative administration of an α-adrenergic blocking agent. Hypotension during Spinal Anesthesia Although phenylephrine has been used both for the prevention and treatment of hypotension resulting from spinal anesthesia, some clinicians state that pure α-adrenergic agonists should not be used because they may further reduce cardiac output. In addition, routine prophylactic use of any vasopressor in spinal anesthesia has been questioned because hypotension does not always occur during spinal anesthesia and treatment can readily be instituted if necessary. It has been suggested that vasopressors be administered prophylactically only in those cases in which a substantial decrease in blood pressure is expected. The use of vasopressors to correct hypotension occurring during anesthesia in obstetrical patients is controversial. Hypotension usually can be minimized by adequate hydration and changing the position of the patient so that the uterus does not compress the inferior vena cava. If a vasopressor is required, ephedrine usually is preferred. Prolongation of Spinal Anesthesia Phenylephrine may be added to solutions of some local anesthetics to decrease the rate of vascular absorption of the anesthetic, thereby localizing anesthesia and prolonging the duration of anesthesia. 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. Paroxysmal Supraventricular Tachycardia Phenylephrine is administered IV to raise blood pressure in order to terminate some attacks of paroxysmal supraventricular tachycardia, especially in patients who are also hypotensive or in shock. Administration of an anticholinesterase drug having a short duration of action (e.g., edrophonium chloride) may be safer, however. 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.114 123 124 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 recent 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 have begun to reformulate various existing 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, are labeled and 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 indicates that topical nasal decongestants (i.e., oxymetazoline) may increase the degree of sinus inflammation,120 potentially delaying resolution of sinusitis.117 Because current labeling for nonprescription (over-the-counter, OTC) nasal decongestant preparations includes use for sinusitis, there are concerns that consumers will assume that nasal decongestants are 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 As a result, the US Food and Drug Administration (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 amending the final monograph for OTC nasal decongestant preparations to remove the indication for relief of nasal congestion associated with sinusitis from labeling and prohibiting use of the term “sinusitis” elsewhere in labeling.117 The compliance date for preparations with annual sales less than $25,000 is October 11, 2007; the compliance date for all other preparations is April 11, 2007.117 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 selfmedication 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 IV phenylephrine has been used to increase blood pressure as an aid in the diagnosis of heart murmurs†. 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. Dosage and Administration Administration Parenteral As a vasopressor, phenylephrine hydrochloride is administered by IM, subcutaneous, or slow IV injection, or IV infusion. The route of administration should be determined by the needs of the individual patient; patients who are in shock may require IV administration to ensure absorption of the drug. For treating hypotension or shock, phenylephrine usually is administered by IV infusion as a dilute solution; however, direct IV injections are administered in treating paroxysmal atrial or nodal tachycardia or in emergencies requiring a strong, immediate pressor effect. In emergencies, phenylephrine may be administered by direct IV injection. For convenience in administration by direct IV injection, 1 mL of the commercially available phenylephrine hydrochloride injection containing 10 mg/mL may be diluted with 9 mL of sterile water for injection to prepare a solution containing 1 mg/mL. For IV infusion, phenylephrine may be diluted with 5% dextrose or 0.9% sodium chloride injection. The concentration of phenylephrine and the infusion rate depend on the drug and fluid requirements of the individual patient. Infusion solutions usually are prepared by adding 10 mg of phenylephrine hydrochloride to 500 mL of diluent. During therapy with a vasopressor, blood pressure should be elevated to slightly less than the patient's normal blood pressure. In previously normotensive patients, systolic blood pressure should be maintained at 80– 100 mm Hg; in previously hypertensive patients, systolic blood pressure should be maintained at 30–40 mm Hg below their usual blood pressure. In some patients with very severe hypotension, maintenance of even lower blood pressure may be desirable if blood or fluid volume replacement has not been completed. Patients receiving the drug by IV infusion should not be left unattended and the infusion flow rate must be closely monitored. Blood pressure should be checked frequently, especially when the drug is administered IV. Phenylephrine therapy should be continued until adequate blood pressure and tissue perfusion are maintained. When IV infusions are discontinued, the infusion rate should be slowed gradually and abrupt withdrawal avoided. The patient should be observed carefully so that therapy may be resumed if the blood pressure falls too rapidly. Pressor therapy should not be reinstated until the systolic blood pressure falls to 70–80 mm Hg. In some patients, additional administration of IV fluids may be necessary before phenylephrine can be discontinued. Oral As a vasoconstrictor for the management of nasal congestion, phenylephrine is administered orally alone or as a fixed-combination decongestant preparation. For self-medication in children receiving phenylephrine orally dissolving strips, the caregiver should be instructed to place the strip on the patient's tongue, where it rapidly dissolves and then can be swallowed.123 124 Topical and Rectal 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 should be administered in the lowest effective dosage for the shortest possible time. When possible, small doses should be injected initially and subsequent doses determined by pressor response. Mild or Moderate Hypotension In treating mild to moderate hypotension in adults, subcutaneous or IM doses range from 1–10 mg; 2–5 mg is most frequently used. The initial adult IM or subcutaneous dose should not exceed 5 mg. Children may receive 0.1 mg/kg or 3 mg/m2 IM or subcutaneously. Additional IM or subcutaneous doses may be given in 1–2 hours if needed. For the treatment of mild to moderate hypotension in adults, the drug may also be administered by slow IV injection in a dose ranging from 0.1–0.5 mg; 0.2 mg is the usual dose. The initial adult IV dose should not exceed 0.5 mg. IV doses may be given no more frequently than every 10–15 minutes. Severe Hypotension or Shock When used as an adjunct in the treatment of severe hypotension or shock, phenylephrine is administered by IV infusion as a dilute solution. (See Dosage and Administration: Administration.) The rate of infusion is adjusted to maintain the blood pressure at the desired level. The drug is usually administered at an initial rate of 0.1–0.18 mg/minute. After the blood pressure stabilizes, 0.04–0.06 mg/minute usually is adequate. If necessary to produce the desired pressor response, additional phenylephrine in increments of 10 mg or more may be added to the infusion solution and the rate of flow adjusted according to the response of the patient. Hypotension during Spinal Anesthesia If phenylephrine is administered prophylactically to prevent hypotension during spinal anesthesia, it should be administered IM or subcutaneously 3– 4 minutes prior to the spinal anesthetic. A dose of 2 mg usually is adequate with low spinal anesthesia in adults, but 3 mg may be necessary with high spinal anesthesia. For hypotensive emergencies during spinal anesthesia in adults, the drug may be given IV in an initial dose of 0.2 mg; any subsequent dose should not exceed the previous dose by 0.1–0.2 mg and a single dose should not exceed 0.5 mg. The manufacturer recommends that 0.044–0.088 mg/kg be administered IM or subcutaneously to treat hypotension during spinal anesthesia in children. Prolongation of Spinal Anesthesia To prolong spinal anesthesia, 2–5 mg of phenylephrine hydrochloride may be added to the anesthetic solution. Vasoconstriction for Regional Anesthesia To produce vasoconstriction in regional anesthesia, the manufacturer states that the optimum concentration of phenylephrine hydrochloride is 0.05 mg/mL (1:20,000). Solutions may be 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. Paroxysmal Supraventricular Tachycardia To terminate attacks of paroxysmal supraventricular tachycardia, phenylephrine is administered rapidly (within 20–30 seconds) by direct IV injection. The manufacturer recommends that the initial dose should not exceed 0.5 mg and that subsequent doses may be increased in increments of 0.1–0.2 mg, depending on the blood pressure response of the patient. Systolic blood pressure should not be raised above 160 mm Hg. The maximum single dose of phenylephrine hydrochloride recommended by the manufacturer is 1 mg. Some clinicians, however, have recommended that 0.5–1 mg be administered rapidly initially and that an additional 2 mg may be given slowly IV if cardiac rhythm fails to revert within 60–90 seconds. 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 Children 6–11 years of age may receive 5 mg of phenylephrine hydrochloride every 4 hours, and children 2–5 years of age may receive 2.5 mg every 4 hours.123 124 (See Cautions: Pediatric Precautions.) The manufacturer states that no more than 6 doses should be administered in a 24-hour period.114 123 124 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.114 123 124 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 Cautions Adverse Effects Systemic Use Phenylephrine 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 hypertension, headache, seizures, cerebral hemorrhage, palpitation, paresthesia, or vomiting. Headache may be a symptom of hypertension. Hypertension may be relieved by administration of an α-adrenergic blocking agent (e.g., phentolamine). If phenylephrine is administered by rapid IV injection in the treatment of paroxysmal supraventricular tachycardia, overdosage may result in short paroxysms of ventricular tachycardia, ventricular extrasystoles, or a sensation of fullness in the head. Phenylephrine can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion, and probably reduced urine output and metabolic acidosis. Severe vasoconstrictive effects may be most likely to occur in hypovolemic patients. In addition, prolonged use of the drug may result in plasma volume depletion that may result in perpetuation of the shock state or the recurrence of hypotension when phenylephrine is discontinued. Phenylephrine can cause severe bradycardia and decreased cardiac output. 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. The drug also increases cardiac work by increasing peripheral arterial resistance and may possibly induce or exacerbate heart failure associated with a diseased myocardium. Some clinicians believe that phenylephrine is contraindicated in shock caused by myocardial infarction. In addition, phenylephrine may increase pulmonary arterial pressure. 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 In patients with shock, pressor 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 phenylephrine is administered. 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. Additional volume replacement also may be required during or after therapy with the drug, especially if hypotension recurs. Monitoring of central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia; in addition, monitoring of central venous or pulmonary arterial diastolic pressure is necessary to avoid overloading the cardiovascular system and precipitating congestive heart failure. 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. 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.114 123 124 In addition, the drug should not be used for selfmedication 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) a monoamine oxidase (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. 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. The drug should be administered with extreme caution to geriatric or hyperthyroid patients or those with bradycardia, partial heart block, myocardial disease, or severe arteriosclerosis. Some clinicians, however, consider severe coronary disease or cardiovascular disease (including myocardial infarction) to be contraindications to use of phenylephrine. Phenylephrine should be administered parenterally with extreme caution if at all to hypertensive patients. Phenylephrine is contraindicated in patients with severe hypertension or ventricular tachycardia and in patients who are hypersensitive to the drug. If administered to patients with acute pancreatitis or hepatitis, the drug may increase ischemia in the liver or pancreas. Phenylephrine should not be used in patients with peripheral or mesenteric vascular thrombosis, because ischemia may be increased and the area of infarction extended. In conjunction with local anesthetics, phenylephrine is contraindicated for use in fingers, toes, ears, nose, or genitalia. 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 selfmedication with an anorectal preparation of the drug if they currently are receiving an antihypertensive agent or antidepressant (e.g., monoamine oxidase inhibitor [MAO] inhibitor).101 102 103 104 105 106 107 108 For additional precautions associated with anorectal phenylephrine therapy, see Dosage and Administration. Pediatric Precautions 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 age;699 the agency continues to assess safety and efficacy of these preparations in older children.702 704 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 recently have agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age.701 702 703 704 Because FDA does not typically request removal of products with previous labeling from pharmacy shelves during a voluntary label change, some preparations will have the new recommendation (“do not use in children younger than 4 years of age”), while others will have the previous recommendation (“do not use in children younger than 2 years of age”).702 704 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.701 702 703 Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage.693 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. Pregnancy and Lactation Pregnancy 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 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.) Animal reproduction studies have not been performed with phenylephrine. It is also not known whether the drug can cause fetal harm when administered to pregnant women. Phenylephrine should be used during pregnancy only when clearly needed. Other pressors (e.g., ephedrine) usually are preferred.132 Lactation Phenylephrine does not appear to be distributed to any great extent into breast milk.121 However, the drug should be used with caution in nursing women. Drug Interactions α- and β-Adrenergic Blocking Agents The vasopressor response to phenylephrine is decreased by prior administration of an α-adrenergic blocking agent such as phentolamine mesylate. Phentolamine may be used to treat hypertension if it occurs during administration of phenylephrine. Phenothiazine drugs have some αadrenergic blocking effects; therefore, prior administration of a phenothiazine may reduce the pressor effect and duration of action of phenylephrine. Larger doses than usual may be required when phenylephrine is used to treat hypotension caused by overdosage of a phenothiazine (e.g., chlorpromazine) or other drugs that block α-adrenergic function. The cardiostimulating effects of phenylephrine are blocked by prior administration of β-adrenergic blocking drugs such as propranolol. Propranolol may be used to treat cardiac arrhythmias occurring during administration of phenylephrine. Oxytocic Drugs When a vasopressor (e.g., phenylephrine) is used in conjunction with oxytocic drugs, the pressor effect is potentiated.132 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 Sympathomimetic Agents Combination products containing phenylephrine and a bronchodilator sympathomimetic agent should not be used concomitantly with epinephrine or other sympathomimetic agents because tachycardia or other serious arrhythmias may occur. 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. The manufacturer states that vasopressors should be used only with extreme caution or not at all with these general anesthetics. However, in usual therapeutic doses, phenylephrine is much less likely to produce arrhythmias than is norepinephrine or metaraminol. Monoamine Oxidase Inhibitors and Drugs Affecting Norepinephrine The cardiac and pressor effects of phenylephrine are potentiated by prior administration of monoamine oxidase (MAO) inhibitors 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 initial doses should be small. 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.) Tricyclic antidepressants (e.g., imipramine) or guanethidine may also potentiate the vasopressor effects of phenylephrine. Other Drugs 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 α-adrenergic receptors. In therapeutic doses, the drug has no substantial stimulant effect on the β-adrenergic receptors of the heart (β1-adrenergic receptors) but substantial activation of these receptors may occur when larger doses are given. Phenylephrine does not stimulate β-adrenergic receptors of the bronchi or peripheral blood vessels (β2-adrenergic receptors). It is believed that α-adrenergic effects result from the inhibition of the production of cyclic adenosine-3′,5′-monophosphate (cAMP) by inhibition of the enzyme adenyl cyclase, whereas β-adrenergic effects result from stimulation of adenyl cyclase activity. Phenylephrine also has an indirect effect by releasing norepinephrine from its storage sites. Although the manufacturer reports that there is no decrease in effectiveness with repeated injections of phenylephrine, some investigators have reported that tachyphylaxis may develop. The main effect of therapeutic doses of phenylephrine is vasoconstriction. Cardiovascular Effects Phenylephrine constricts resistance and, to a lesser degree, capacitance blood vessels by its effects on α-adrenergic receptors. Total peripheral resistance is increased, resulting in increased systolic and diastolic blood pressure. Venous return to the heart may be decreased; however, phenylephrine increases venous pressure slightly. Blood flow to vital organs, skin, and probably skeletal muscle is reduced. 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. Constriction of renal blood vessels by phenylephrine decreases 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. 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. When administered by oral inhalation (preparations for oral inhalation no longer are commercially available in the US), phenylephrine reduces bronchiolar blood flow and shrinks swollen membranes, thereby reducing edema and congestion. When used in conjunction with a bronchodilator by oral inhalation, phenylephrine-induced vasoconstriction slows the absorption of the bronchodilator and prolongs its duration of action. Following oral administration or topical application of phenylephrine to the mucosa, constriction of blood vessels in the nasal mucosa may relieve nasal congestion. The main effect of phenylephrine on the heart is bradycardia, which results from increased vagal activity occurring as a reflex to increased arterial blood pressure. Bradycardia occurs after parenteral administration of usual therapeutic doses and also may result from overdosage via oral inhalation. Attacks of paroxysmal atrial or nodal tachycardia may be ended by the decrease in sympathetic cardioaccelerator tone and increase in parasympathomimetic cardiodecelerator tone. Bradycardia is blocked by atropine; if phenylephrine is administered after atropine, a slight increase in heart rate may occur. In some patients, phenylephrine has caused a paradoxical increase in heart rate when administered to treat hypotension occurring after spinal anesthesia. Phenylephrine acts on β1-adrenergic receptors in the heart, producing a positive inotropic effect on the myocardium only at doses greater than those usually used therapeutically. Cardiac output is decreased slightly, probably as a result of the reflex bradycardia. Phenylephrine constricts coronary blood vessels but increases coronary blood flow, probably as a result of increased systemic blood pressure. An increase in myocardial oxygen uptake has been demonstrated following administration of phenylephrine in animals, and the drug increases the work of the heart by increasing peripheral arterial resistance. However, phenylephrine does not appear to decrease cardiac efficiency. Rarely, the drug may increase the irritability of the heart, causing arrhythmias such as atrioventricular nodal rhythm, premature ventricular beats, ventricular tachycardia, or ventricular extrasystoles. Phenylephrine constricts cerebral blood vessels but increases cerebral blood flow in hypotensive patients, probably secondary to increased systemic blood pressure. 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 (firstpass) 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 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 elimination half-life of phenylephrine averages 2–3 hours following oral or IV administration.121 122 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 Chemistry and Stability Chemistry Phenylephrine is a sympathomimetic amine that is pharmacologically similar to methoxamine hydrochloride. Phenylephrine is commercially available as the hydrochloride. Phenylephrine hydrochloride occurs as odorless, white or practically white crystals having a bitter taste and is freely soluble in water and in alcohol. Phenylephrine hydrochloride injection has a pH of 3.0–6.5. Phenylephrine bitartrate occurs as a white, crystalline powder and is soluble in water and insoluble in alcohol. Commercially available phenylephrine hydrochloride injections may contain the antioxidant, sodium metabisulfite, and the air in the ampuls has been replaced by nitrogen to prevent oxidation. Stability Phenylephrine hydrochloride and solutions containing the drug are subject to oxidation and should be stored in tight, light-resistant containers. Solutions of the drug must not be used if they are brown or contain a precipitate. However, oxidation of the drug resulting in loss of activity may occur without a color change being evident. Solutions of phenylephrine hydrochloride that have been diluted in 5% dextrose injection are stable for at least 48 hours at pH 3.5–7.5. Although phenylephrine has been reported to be incompatible with alkalies, the drug is stable for at least 48 hours when diluted to 0.02 mg/mL with 5% sodium bicarbonate injection. Phenylephrine is incompatible with ferric salts, oxidizing agents, or metals. Phenylephrine hydrochloride oral tablets should be stored at 15–25°C in a dry place;114 orally dissolving strips should be stored at 20–25°C.123 124 Phenylephrine hydrochloride injections should be stored at room temperature up to 30°C and protected from light. Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Many prescription cough, cold, and allergy preparations commercially available in the US have not been approved by the US Food and Drug Administration (FDA).500 Because of the potentially serious health risks associated with unapproved preparations, FDA announced on March 3, 2011, that it would take enforcement action (e.g., seizure, injunction, other judicial or administrative proceeding) against any currently marketed and listed unapproved cough, cold, and allergy preparation manufactured on or after June 1, 2011 or shipped on or after August 30, 2011.500 For additional information and for a complete list of unapproved cough, cold, and allergy preparations affected by this FDA notice, see FDA website ([Web]). Phenylephrine Hydrochloride Routes Dosage Forms Brand Strengths Names Manufacturer Oral Tablets 10 mg Sudafed PE® Congestion McNeil Parenteral Injection 10 mg/mL* Generic Name: Phenylephrine Hydrochloride Injection Topical Cream 0.25% Preparation with H® Glycerin 14.4%, Petrolatum 15%, and Pramokine 1% Pfizer Gel 0.25% Preparation with Witch H® Pfizer Routes Dosage Forms Brand Strengths Names Manufacturer Hazel 50% Ointment 0.25% Preparation with H® Mineral Oil 14%, Petrolatum 71.9% Suppository 0.25% with Cocoa Butter 85.39% Preparation H® Pfizer Pfizer * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Phenylephrine Hydrochloride Combinations Dosage Routes Forms Oral Strengths Brand Names Manufacturer Capsules, 5 mg with (liquidAcetaminophen filled) 325 mg and Dextromethorphan Hydrobromide 10 mg Vicks® Procter & ® DayQuil Gamble Cold & Flu Relief LiquiCaps For Solution 10 mg/packet with Acetaminophen 325 mg/packet and Pheniramine Maleate 20 mg/packet Theraflu® Cold & Sore Throat Novartis 10 mg/packet with Acetaminophen 650 mg/packet and Dextromethorphan Theraflu® Daytime Severe Cold & Cough Novartis Dosage Routes Forms Strengths Brand Names Manufacturer Hydrobromide 20 mg 10 mg/packet with Theraflu® Novartis Acetaminophen Flu & Sore 650 mg/packet Throat and Pheniramine Maleate 20 mg/packet 10mg/packet with Acetaminophen 650 mg/packet and Diphenhydramine Hydrochloride 25 mg Solution Theraflu® Nighttime Severe Cold & Cough Novartis 10 mg/packet with Theraflu® Dextromethorphan Cold & Hydrobromide 20 Cough mg/packet and Pheniramine Maleate 20 mg/packet Novartis 5 mg/15 mL with Acetaminophen 325 mg/15 mL and Dextromethorphan Hydrobromide 10 mg/15 mL Novartis Theraflu Warming Relief® Daytime Severe Cold & Cough Tylenol® McNeil Cold MultiSymptom Daytime Citrus Burst® Liquid Vicks® DayQuil® Procter & Gamble Dosage Routes Forms Strengths Brand Names Manufacturer Cold & Flu Relief 5 mg/15 mL with Acetaminophen 325 mg/15 mL and Diphenhydramine Hydrochloride 12.5 mg/15 mL Theraflu® Novartis Warming Relief® Flu & Sore Throat Theraflu® Warming Relief® Nighttime Severe Cold & Cough 2.5 mg/5 mL with Children's Acetaminophen Tylenol® 160 mg/5 mL and Plus Cold Chlorpheniramine Maleate 1 mg/5 mL Novartis McNeil 2.5 mg/5 mL with Acetaminophen 160 mg/5 mL and Chlorpheniramine Maleate 1 mg/5 mL, and Dextromethorphan Hydrobromide 5 mg/5mL Children's McNeil Tylenol® Plus MultiSymptom Cold 2.5 mg/5 mL with Acetaminophen 160 mg/5 mL and Diphenhydramine Hydrochloride 12.5 mg/5 mL Children's Tylenol® Plus Cold & Allergy 2.5 mg/5 mL with Triaminic® McNeil Novartis Dosage Routes Forms Strengths Brand Names Manufacturer Chlorpheniramine Maleate 1 mg/5 mL Cold & Allergy 2.5 mg/5 mL with Dextromethorphan Hydrobromide 5 mg/5mL Children's McNeil Sudafed PE® Cold & Cough Triaminic® Day Time Cold & Cough 2.5 mg/5mL with Diphenhydramine Hydrochloride 6.25 mg/5 mL Novartis Triaminic® Novartis Night Time Cold & Cough 2.5 mg/5 mL with Triaminic® Novartis Guaifenesin 50 Chest & mg/5mL Nasal Congestion Strips, 2.5 mg with orally Dextromethorphan dissolving 3.67 mg (equivalent to Dextromethorphan Hydrobromide 5 mg) Tablets Triaminic Thin Strips® Day Time Cold & Cough Novartis 5 mg with Diphenhydramine Hydrochloride 12.5 mg Triaminic Novartis Thin Strips® Night Time Cold & Cough 5 mg with Acetaminophen 325 mg, Chlorpheniramine Maleate 2 mg, and Theraflu® Warming Relief Caplets® Nighttime Novartis Dosage Routes Forms Strengths Brand Names Manufacturer Dextromethorphan MultiHydrobromide 10 Symptom mg Cold Tablets, filmcoated 5 mg with Acetaminophen 325 mg and Dextromethorphan Hydrobromide 10 mg Theraflu Warming Relief Caplets ® Daytime MultiSymptom Cold Novartis 10 mg with Chlorpheniramine Maleate 4 mg Sudafed PE® Sinus + Allergy McNeil 5 mg with Acetaminophen 325 mg Excedrin® Sinus Headache Novartis Sudafed McNeil ® PE Pressure + Pain Caplets 5 mg with Acetaminophen 325 mg, Chlorpheniramine Maleate 2 mg, and Dextromethorphan Hydrobromide 10 mg Tylenol® McNeil Cold Head Congestion Nighttime Cool Burst® Caplets 5 mg with Acetaminophen 325 mg and Dextromethorphan Hydrobromide 10 mg Tylenol® McNeil Cold Head Congestion Daytime Cool Burst® Caplets Dosage Routes Forms Strengths Brand Names Manufacturer 5 mg with Acetaminophen 325 mg, Dextromethorphan Hydrobromide 10 mg, and Guaifenesin 100 mg Sudafed McNeil PE® Cold + Cough Caplets 5 mg with Acetaminophen 325 mg, Dextromethorphan Hydrobromide 10 mg, and Guaifenesin 200 mg Tylenol® McNeil Cold Head Congestion Severe Cool Burst® Caplets 5 mg with Acetaminophen 325 mg and Diphenhydramine Hydrochloride 12.5 mg Sudafed McNeil ® PE Severe Cold Caplets 5 mg with Guaifenesin 200 mg Sudafed PE® NonDrying Sinus Caplets McNeil Comparative Pricing This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays. Donatussin 10-2-15-100MG/5ML Syrup (LASER PHARMACEUTICALS): 473/$36.25 or 1419/$108.75 Duraphen Forte 30-30-1200MG 12-hr Tablets (KOWA PHARMACEUTICALS AMERICA): 100/$135.98 or 300/$375.97 Duratuss AC 12 15-12.5-15MG/5ML Suspension (VICTORY PHARMA): 473/$215.99 or 1419/$609.96 Promethazine VC Plain 6.25-5MG/5ML Syrup (QUALITEST): 473/$39.99 or 1419/$109.97 R-Tanna 9-25MG Tablets (PRASCO LABORATORIES): 30/$39.99 or 90/$109.97 Rynatan 9-25MG Tablets (MEDA PHARMACEUTICALS): 30/$122.99 or 90/$349.97 Rynatan Pediatric 4.5-5MG/5ML Suspension (MEDA PHARMACEUTICALS): 120/$105.99 or 360/$299.96 AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions November 4, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. † Use is not currently included in the labeling approved by the US Food and Drug Administration. References Only references cited for selected revisions after 1984 are available electronically. 1. 101. Food and Drug Administration. Anorectal drug products for over-thecounter human use. [21 CFR Part 346] 2003 April 1. 2. 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. 3. 103. Wyeth. Preparation H® (cream) prescribing information. From Wyeth website. 2003. 4. 104. Wyeth. Preparation H® (ointment) prescribing information. From Wyeth website. 2003. 5. 105. Wyeth. Preparation H® (gel) prescribing information. From Wyeth website. 2003. 6. 106. Wyeth. Preparation H® (suppositories) prescribing information. From Wyeth website. 2003. 7. 107. Food and Drug Administration. Anorectal drug products for over-thecounter human use: final monograph. [21 CFR Parts 310, 346, and 369] Fed Regist. 1990; 55:31776. 8. 108. Food and Drug Administration. Anorectal drug products for over-thecounter human use: establishment of a monograph. Fed Regist. 1980; 45:35576-35677. 9. 109. National Association of Chain Drug Stores. State methamphetamine precursor laws. From the NACDS website. Accessed October 3, 2005. 10. 110. National Alliance for Model State Drug Laws. Methamphetamine Information. From the Alliance website. Accessed October 3, 2005. 11. 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. 12. 112. Anon. Senate approves anti-meth bill. CBS News, 2005 Sep 10. From CBS news website. 13. 113. Novartis, East Hanover, NJ: Personal communication. 14. 114. Pfizer. Sudafed PE® nasal decongestant (phenylephrine hydrochloride) tablets product information. From Pfizer website. Accessed October 17, 2005. 15. 115. Hendeles L. Selecting a decongestant. Pharmacotherapy. 1993; 13:129S-134S. [PubMed] [IDIS 323175] 16. 116. Pfizer, Morris Plains, NJ: Personal communication. 17. 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. 18. 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] 19. 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] 20. 120. Benninger MS, Anon J, Mabry RL. The medical management of rhinosinusitis. Otolaryngol Head Neck Surg. 1997; 117:(Suppl) S41-9. 21. 121. Kanfer I, Dowse R, Vuma V. Pharmacokinetics of oral decongestants. Pharmacotherapy. 1993; 13:(Suppl) 116-28S. 22. 122. Hengstmann JH, Goronzy J. Pharmacokinetics of 3H- phenylephrine in man. Eur J Clin Pharmacol. 1982; 21:335-41. [PubMed] 23. 123. Novartis. Triaminic® (phenylephrine hydrochloride) Infant Thin Strips® Decongestant product information. From Novartis Triaminic website. Accessed October 18, 2006. 24. 124. Novartis. Triaminic® (phenylephrine hydrochloride) Thin Strips® Cold product information. From Novartis Triaminic website. Accessed October 18, 2006. 25. 125. Hendeles L, Hatton RC. Oral phenylephrine: an ineffective replacement for pseudoephedrine?. J Allergy Clin Immunol. 2006; 118:27980. [PubMed] 26. 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. 27. 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. 76N052N] Fed Regist. 1985; 50:2220-41. 28. 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. 29. 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. 30. 130. Anon. Makers pull cold medicines sold for infants. CNN News, 2007 Oct 11. From CNN.com website. 31. 131. Ligand Pharmaceuticals. Avinza® (morphine sulfate) extended- release capsules prescribing information. San Diego, CA. 2003 Feb. 32. 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. 33. 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. 34. 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. 35. 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. 36. 136. Procter & Gamble. Vicks® Dayquil® Cold & Flu (acetaminophen, dextromethorphan hydrobromide, and phenylephrine hydrochloride) Liquicaps patient information. From Procter & Gamble website. Accessed 2008 Feb 25. 37. 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. 38. 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. 39. 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. 40. 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. AHFS Drug Information © American Society of Health-System Pharmacists 2013 MedicinesComplete © The Pharmaceutical Press 2013