VA Class:AU100

VA Class:RE200

AHFS Class:

• alpha- and beta-Adrenergic Agonists 12:12.12

Generic Name(s):

• Pseudoephedrine Hydrochloride

• Pseudoephedrine Sulfate

Chemical Name:

• [ S -( R *, R *)]-α-[1-(Methylamino)ethyl]-benzenemethanol hydrochloride

• [ S -( R *, R *)]-α-[1-(Methylamino)ethyl]-benzenemethanol sulfate

Molecular Formula:

• C₁₀H₁₅NO • HCl

• C₁₀H₁₅NO • H₂SO₄

Pseudoephedrine is a sympathomimetic agent that occurs naturally in plants of the genus Ephedra ; the drug acts directly on both α- and, to a lesser degree, β-adrenergic receptors.

Pseudoephedrine is used as a nasal decongestant for self-medication for the temporary relief of nasal congestion associated with upper respiratory allergy and to provide temporary relief of sinus congestion and pressure.108,109,110,111,112 The drug also has been used for self-medication in the symptomatic prevention of otitic barotrauma† (aerotitis [ barotitis] media).119,120,121 Pseudoephedrine also has been misused for clandestine synthesis of methamphetamine and methcathinone for illicit use.100,101,102,113

Nasal Congestion and Other Respiratory Conditions

Pseudoephedrine is used as a nasal decongestant for self-medication for the temporary relief of nasal congestion associated with upper respiratory allergy (e.g., hay fever) or the common cold;108,109,110,111,112 the drug also is used to provide temporary relief of sinus congestion and pressure.109,110,111,112 Preparations containing pseudoephedrine in fixed combination with other agents (e.g., acetaminophen, brompheniramine, chlorpheniramine, desloratadine, dextromethorphan, fexofenadine, guaifenesin, ibuprofen, loratadine, methscopolamine, triprolidine) are used for relief of nasal/sinus congestion and pressure and/or other symptoms (e.g., rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, cough, fever) associated with seasonal or perennial allergic rhinitis, nonallergic (vasomotor) rhinitis, other upper respiratory allergies, or the common cold.154,156,157,158,159,161,162,163,164,165

In clinical studies, oral pseudoephedrine administered as single 60-mg doses was effective in relieving congestion.145,146,147,148,149 Unlike topically applied decongestants, pseudoephedrine produces little if any rebound congestion. In patients with otic inflammation or infection, the drug may be useful in opening obstructed eustachian ostia. Pseudoephedrine may be used as an adjunct to analgesics, antihistamines, antitussives, expectorants, or antibiotics when indicated.

Nasal decongestants, including pseudoephedrine, are labeled and have been used for self-medication for the temporary relief of nasal congestion associated with sinusitis.109,110,135 However, prospective studies of nasal decongestants for this use are lacking,136 and data on their use as adjunctive therapy in the management of sinusitis are limited and controversial.135,137 Furthermore, evidence from an animal study indicates that topical nasal decongestants (i.e., oxymetazoline) may increase the degree of sinus inflammation,138 potentially delaying resolution of sinusitis.135 Because current labeling for non (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).135 As a result, the US Food and Drug Administration (FDA) no longer considers oral or topical nasal decongestants appropriate for self-medication of sinusitis.135 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 congestion associated with sinusitis from labeling and prohibiting use of the term sinusitis elsewhere in labeling.135 The compliance date for preparations with annual sales less than $25,000 was October 11, 2007; the compliance date for all other preparations was April 11, 2007.135

Although pseudoephedrine has been used in the symptomatic treatment of bronchial asthma and reversible bronchospasm, the drug appears to be ineffective as a bronchodilator.

As part of its ongoing review of over-the-counter drug products, the FDA has determined that pseudoephedrine in combination with caffeine is not generally recognized as safe and effective for over-the-counter use.105 Such a combination introduced or initially delivered for introduction into interstate commerce after October 29, 2001, is considered by the FDA to be a new drug and misbranded, and cannot be marketed for over-the-counter use unless it is the subject of an approved new drug application.105

Although cough and cold preparations that contain nasal decongestants, antihistamines, cough suppressants, and/or expectorants commonly were used in pediatric patients younger than 2 years of age, systematic reviews of controlled trials have concluded that non (over-the-counter, OTC) cough and cold preparations are no more effective than placebo in reducing acute cough and other symptoms of upper respiratory tract infection in these patients.150 Furthermore, adverse events, including deaths, have been (and continue to be) reported in pediatric patients younger than 2 years of age receiving these preparations.150 (See Cautions: Pediatric Precautions.) Therefore, the US Centers for Disease Control and Prevention (CDC) state that, as an alternative to pseudoephedrine and other nasal decongestants, caregivers may consider using a rubber suction bulb to clear nasal congestion and using saline nasal drops or a cool-mist humidifier to soften secretions in infants.150

Otitic Barotrauma

Pseudoephedrine has been used orally for self-medication in the symptomatic prevention of otitic barotrauma† (aerotitis [ barotitis] media).119,120,121 Otitic barotrauma, commonly known as middle ear squeeze, refers to tissue damage caused by failure of the middle ear to equilibrate its internal pressure to accommodate changes in atmospheric pressure (e.g., during descent of an aircraft, underwater diving, hyperbaric oxygenation).119,120,121,122,123,125 Clinical manifestations include a sensation of otic blockage or discomfort, otalgia, tinnitus, vertigo, and transient conductive hearing loss; these manifestations may be accompanied by tympanic membrane congestion or hemorrhage, hemotympanum, or membrane perforation or rupture.119,120,121 Although few controlled clinical studies have been conducted, oral (e.g., pseudoephedrine) or nasal (e.g., oxymetazoline) decongestants generally have been recommended for prevention or treatment of otitic barotrauma.119,120,121,123,125

Prophylactic treatment with pseudoephedrine appears to be effective in preventing otitic barotrauma associated with air travel in adults†.119,120,121 In a randomized, double-blind, placebo-controlled study in a limited number of healthy adults with a history of otic discomfort during air travel, administration of extended-release pseudoephedrine hydrochloride (120 mg) at least 30 minutes before flight departure was associated with a lower incidence of otitic barotrauma; approximately 32% of individuals receiving pseudoephedrine reported manifestations of otitic barotrauma (e.g., blockage, hearing loss) compared with 62% of those receiving placebo.119 In a randomized, double-blind, comparative study, pseudoephedrine appeared to be more effective than oxymetazoline, which was no more effective than placebo, in reducing the incidence of otitic barotrauma.120 Manifestations of otitic barotrauma (e.g., otalgia, blockage) reportedly occurred in 34, 64, or 71% of healthy adults receiving extended-release pseudoephedrine hydrochloride126 (120 mg) tablets, oxymetazoline hydrochloride (0.05%) nasal spray, or placebo, respectively, at least 30 minutes before flight departure.120

Efficacy of pseudoephedrine in preventing otitic barotrauma associated with air travel in children† has not been established.124 In a randomized, double-blind, placebo-controlled study in a limited number of children 6 months to 6 years of age, administration of pseudoephedrine hydrochloride oral solution (1 mg/kg) 30-60 minutes before flight departure did not decrease the incidence of otic pain during either ascent (4 vs 5% of children treated with pseudoephedrine or placebo, respectively) or descent (12 vs 13% of those receiving pseudoephedrine or placebo, respectively) of the aircraft.124 Furthermore, prophylactic treatment with pseudoephedrine was associated with a higher incidence of drowsiness during takeoff; drowsiness was reported in 60% of children receiving pseudoephedrine compared with 27% of those receiving placebo.124 Treatment with pseudoephedrine was not associated with drowsiness during descent or with excitability during ascent of the aircraft.124

Limited data indicate that pseudoephedrine may be more effective than placebo in preventing otitic barotrauma associated with underwater diving †.121 In one randomized, double-blind, placebo-controlled study in a limited number of first-time underwater divers, approximately 8% of individuals receiving pseudoephedrine hydrochloride (60 mg) 30 minutes before diving reported otic discomfort and blockage compared with 32% of those receiving placebo.121

Although additional study is needed, the limited data available suggest that pseudoephedrine may be useful in the symptomatic prevention of otitic barotrauma associated with aircraft descent or underwater diving in adults.119,120,121,126 However, evidence to support such use of intranasal oxymetazoline is lacking.126

Misuse and Abuse

Because pseudoephedrine has been used in the clandestine synthesis of methamphetamine and methcathinone, both CNS stimulants with great potential for habituation and physical and/or psychic dependence, the US enacted the Comprehensive Methamphetamine Control Act of 1996 (US Public Law 104-237)100,101,102,113 and later the Methamphetamine Anti-Proliferation Act (MAPA [US Public Law 106-310], title XXXVI of the Children's Health Act of 2000)114,115 to reduce the potential for misuse (diversion) of pseudoephedrine. MAPA, effective October 2001, limited retail sales (including mail-order distribution) of pseudoephedrine-containing drug products to 9 g (in terms of the base) for a single transaction and limited the package size to no more than 3 g of pseudoephedrine (in terms of the base).114,115 Neither law regulated “ordinary over-the-counter (OTC) pseudoephedrine drug products,” which have been defined as products containing no more than 3 g of pseudoephedrine (in terms of the base), packaged in blister or unit-dose packs of 1 or 2 dosage units per pack or as packaged-size liquid preparations.100,101,102,113,114 As of October 1997, transactions of pseudoephedrine by mail-order pharmacies must be reported monthly to the US Attorney General according to applicable regulations.100,101,102,142

Despite the enactment of MAPA, methamphetamine abuse remains a serious problem.127,144 In March 2006, the Combat Methamphetamine Epidemic Act (CMEA) of 2005 (Title VII of the USA Patriot Act Improvement and Reauthorization Act of 2005) was signed into law, which effectively amends the Federal Controlled Substances Act of 1970 to tighten control over the sale and distribution of non pseudoephedrine and ephedrine.130,139,140,141 This law created a new class of products called “scheduled listed chemical products,” which are defined in the law as products containing pseudoephedrine, ephedrine, or phenylpropanolamine (no longer commercially available in the US) or any salt, optical isomer, or salt of an optical isomer of these drugs that are lawful non products in the US, and set additional requirements for their sale.140,142 Effective September 30, 2006, the law requires pharmacies and other retail distributors to store pseudoephedrine- and ephedrine-containing preparations behind the counter or in locked cabinets; requires purchasers to provide approved photographic identification and sign a written or electronic logbook for each purchase; requires pharmacies and other retail distributors to keep information about the purchasers (e.g., name, address, signature) and purchases (e.g., name of product, quantity sold, date and time of sale) for at least 2 years; and limits the amount that can be purchased to no more than 3.6 g per day or 9 g per month.130,131,139,140,141 The law exempts the requirements for a written or electronic log for any purchase of single-dose packages that contain no more than 60 mg of pseudoephedrine; however, these single-dose packages also must be stored behind the counter.139,140 To comply with CMEA, pharmacies and other retail distributors selling preparations containing pseudoephedrine are required to submit to the Attorney General a statement regarding self-certification and employee training on this new law and to maintain records relating to such training at their place of operation.139,140 Additional information about legal and regulatory requirements under CMEA may be obtained at the website of the Office of Diversion Control of the US Drug Enforcement Administration (DEA) ([Web]), including specific requirements for various sellers (e.g., pharmacies, mail-order sellers) and employee training materials developed by DEA.142,143,144

Use of pseudoephedrine in some states may be subject to additional controls, since some states had restricted the , dispensing, and distribution of pseudoephedrine (e.g., as a controlled substance or a drug) prior to passage of the federal law.128,129,139 For example, in the state of Oregon, legislation was enacted in August 2005 that required the Oregon State Board of Pharmacy to classify pseudoephedrine, ephedrine, and phenylpropanolamine as schedule III drugs by July 2006, which effectively moved these drugs from the non to the -only category in that state.127 Where such state laws are more stringent than the provisions of CMEA, the state requirements also must be followed.139,142,143,144

In response to such restrictions, some manufacturers have voluntarily reformulated various existing pseudoephedrine-containing preparations, replacing the pseudoephedrine component with other decongestants such as phenylephrine.132,139

Administration

Pseudoephedrine hydrochloride and sulfate are administered orally.108,109,110,111,112

Pseudoephedrine hydrochloride 240-mg extended-release tablets should be administered orally once daily and swallowed whole with water; the extended-release tablets should not be divided, crushed, chewed, or dissolved.110 Patients should be advised that the tablet does not completely dissolve and may be passed in the stool.110

Dosage

Nasal Congestion and Other Respiratory Conditions

The usual dosage of pseudoephedrine hydrochloride for adults and children 12 years of age or older is 60 mg every 4-6 hours with a maximum of 240 mg daily.108

Children 6-11 years of age may receive 30 mg of pseudoephedrine hydrochloride every 4-6 hours with a maximum dosage of 120 mg daily, and children 2-5 years of age may receive 15 mg every 4-6 hours with a maximum dosage of 60 mg daily.108,111,112 Alternatively, some pediatricians recommend 4 mg/kg or 125 mg/m² daily, given in 4 divided doses. For children younger than 2 years of age, a pediatrician should be consulted. Suggested dosages for children younger than 2 years of age† for some cough and cold preparations have been published in various references for prescribing and parenting.150 Using recommended dosages for adults and older children, some clinicians have extrapolated dosages for these preparations based on the weight or age of children younger than 2 years of age.150 However, these extrapolations were based on assumptions that pathology of the disease and pharmacology of the drugs are similar in adults and pediatric patients.150,108,111,112 There currently are no specific dosage recommendations (i.e., approved by US Food and Drug Administration [FDA]) for cough and cold preparations for this patient population.150 (See Cautions: Pediatric Precautions.)

When an extended-release preparation of pseudoephedrine hydrochloride is used, adults and children 12 years of age or older may receive 120 mg of the drug every 12 hours109 or 240 mg every 24 hours.110 The manufacturer recommends that this dosage not be exceeded.110

For self-medication , the manufacturers recommend that patients discontinue the drug and consult a clinician if symptoms persist for longer than 7 days or are accompanied by fever.108,109,110,111,112 (See Cautions: Precautions and Contraindications.)

Otitic Barotrauma

For self-medication to prevent otitic barotrauma†, pseudoephedrine hydrochloride has been given orally at a dosage of 120 mg (as the extended-release tablets) in adult air travelers or 60 mg in adult underwater divers; in clinical studies, the drug was administered 30 minutes before flight departure in air travelers or 30 minutes before diving in underwater divers.119,120,121

Adverse Effects

Because pseudoephedrine is a sympathomimetic agent, the possibility of adverse effects associated with other sympathomimetic drugs, including fear, anxiety, tenseness, tremor, hallucinations, seizures, pallor, respiratory difficulty, dysuria, and cardiovascular collapse should be considered. Large doses of pseudoephedrine may cause lightheadedness, nausea, and/or vomiting.

CNS Effects

Pseudoephedrine may cause mild CNS stimulation, especially in patients who are hypersensitive to the effects of sympathomimetic drugs. Nervousness, excitability, restlessness, dizziness, weakness, and insomnia may occur. Headache and drowsiness also have been reported.

Cardiovascular Effects

Although oral administration of usual doses of pseudoephedrine to normotensive patients usually produces negligible pressor effects, the drug should be used with caution in hypertensive patients. Pseudoephedrine may increase the irritability of the heart muscle and may alter the rhythmic function of the ventricles, especially in large doses or when administered to patients who are hypersensitive to the myocardial effects of sympathomimetic drugs. Tachycardia or palpitation may occur. One patient who received 120 mg of pseudoephedrine hydrochloride every 4 hours developed multifocal premature ventricular contractions which disappeared within a few days after the drug was discontinued. In addition, pseudoephedrine may have precipitated an attack of atrial fibrillation in an infant. It was postulated that the patient may have had previously unsuspected idiopathic atrial fibrillation, and therefore may have been especially sensitive to the myocardial effects of the drug.

Dermatologic and Sensitivity Reactions

Fixed dermatologic eruptions (erythematous nummular patches) developed in 2 patients after a combination containing 60 mg of pseudoephedrine hydrochloride and 2.5 mg of triprolidine hydrochloride was administered. Sensitivity testing indicated that pseudoephedrine was the cause of this reaction.

Ocular Effects

In one patient with latent Horner's syndrome, administration of pseudoephedrine in combination with triprolidine caused anisocoria.

Precautions and Contraindications

As with other sympathomimetic drugs, pseudoephedrine should not be used for self-medication in patients with hyperthyroidism, diabetes mellitus, hypertension, ischemic heart disease, or difficulty urinating secondary to prostatic hypertrophy without consulting a clinician.108,109,110,111,112 The drug should be used cautiously, and may be contraindicated, in patients who are hypersensitive to the effects of other sympathomimetic drugs. Pseudoephedrine is contraindicated in patients with severe hypertension, severe coronary artery disease, angle-closure glaucoma, or urinary retention.133 Pseudoephedrine also is contraindicated in patients currently receiving, or having recently received (i.e., within 2 weeks), a monoamine oxidase (MAO) inhibitor.108,109,110,111,112 (See Drug Interactions: Monoamine Oxidase Inhibitors.)

The possibility that pseudoephedrine hydrochloride 240-mg extended-release tablets rarely can cause GI obstruction, particularly in patients with severe narrowing of the esophagus, stomach, or intestine, should be considered.110 Patients with GI obstruction or narrowing should not use the 240-mg extended-release tablets without consulting a clinician.110

Unless otherwise directed by a clinician, patients receiving pseudoephedrine for self-medication should be advised to discontinue the drug if nervousness, dizziness, or insomnia develops during therapy, or if symptoms persist for longer than 7 days or are accompanied by fever.108,109,110,111,112 Patients receiving pseudoephedrine hydrochloride 240-mg extended-release tablets should be advised to discontinue the drug and consult a clinician if persistent abdominal pain or vomiting occurs.110

The potential for misuse or abuse of pseudoephedrine should be considered. (See Uses: Misuse and Abuse.)

When pseudoephedrine is used in fixed combination with other agents, the cautions, precautions, and contraindications associated with the concomitant agent(s) should be considered.154,156,157,158,159,161,162,163,164,165

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that each 15-mg chewable tablet of Sudafed^® Children's Nasal Decongestant contains aspartame (NutraSweet^®) which is metabolized in the GI tract to provide about 0.78 mg of phenylalanine following oral administration.111

Pediatric Precautions

The extended-release preparations containing 120 mg of pseudoephedrine hydrochloride or sulfate or 240 mg of pseudoephedrine hydrochloride should not be administered to patients younger than 12 years of age.109,110 An increased incidence of drowsiness was reported in children who received pseudoephedrine hydrochloride (1 mg/kg) compared with those who received placebo before air travel (60 vs 27%, respectively).124

Death has been reported rarely in pediatric patients younger than 2 years of age receiving cough and cold preparations.150 In a report published by the US Centers for Disease Control and Prevention (CDC), cough and cold preparations were determined by medical examiners or coroners to be the underlying cause of death in 3 infants 6 months of age or younger during 2005.150,151 According to the report, all 3 of these infants had received and/or OTC preparations that contained pseudoephedrine, and 2 of the infants received preparations containing carbinoxamine.150 Postmortem examination revealed high blood concentrations of pseudoephedrine (i.e., 9-14 times higher than those achieved following administration of recommended dosages of pseudoephedrine in children 2-12 years of age) in all 3 of the infants, detectable blood concentrations of acetaminophen and dextromethorphan in 2 of the infants, and detectable blood concentrations of doxylamine in one of the infants.150 Because few data exist regarding the therapeutic or toxic concentrations of cough and cold medications in pediatric patients younger than 2 years of age and because there are no universally accepted criteria for attributing deaths to cough and cold preparations, the cause of death in these infants was based on the report of the medical examiner or coroner.150 However, the actual cause of death might have been overdosage of one drug, interaction of different drugs, an underlying medical condition, or a combination of drugs and underlying medical conditions.150 In addition to these 3 deaths, an estimated 1519 children younger than 2 years of age were treated in emergency departments in the US during 2004-2005 for adverse events, including overdoses, associated with cold and cough preparations.150

The dosages at which cough and cold preparations can cause illness or death in pediatric patients younger than 2 years of age are not known, and there are no specific dosage recommendations (i.e., approved by the US Food and Drug Administration [FDA]) for the symptomatic treatment of cold and cough for patients in this age group.150 (See Dosage and Administration: Dosage.) Because of the absence of dosage recommendations, limited published evidence of effectiveness, and risks for toxicity (including fatal overdosage), FDA stated that non 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 non cough and cold preparations to avoid overdosage.

Geriatric Precautions

Geriatric patients may be especially sensitive to the effects of sympathomimetic amines. Overdosage of sympathomimetic amines in patients older than 60 years of age may cause hallucinations, CNS depression, seizures, and death. Extended-release preparations containing pseudoephedrine, therefore, should not be administered to these patients until safety has been established by administration of a short-acting preparation.

Pregnancy and Lactation

Sympathomimetic amines have been shown to be teratogenic in some animal species.117 However, use of pseudoephedrine during pregnancy to date has not been definitely associated with any specific congenital malformations.117,118

Pseudoephedrine distributes into and is concentrated in breast milk.104,106,107 About 0.5% of an oral dose is distributed into breast milk over 24 hours.104,107 In a limited study, milk-to-plasma concentration ratios were 3.3, 3.9, and 2.6 at 1, 3, and 12 hours, respectively, following administration of a single oral dose of the drug to nursing women.107 Although milk concentrations of pseudoephedrine are expected to be somewhat greater with multiple-dose administration of the drug, some experts state that the actual amounts of the drug distributed in breast milk are not high enough to warrant cessation of nursing.107 The American Academy of Pediatrics (AAP) states that no change in the nursing infant has been observed while the mother was ingesting pseudoephedrine and that the drug usually is compatible with breast-feeding.106

Sympathomimetic Agents

Pseudoephedrine should be administered with extreme caution, if at all, with other sympathomimetic agents because of the possibility of additive effects and increased toxicity.

Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) inhibitors, by increasing the quantity of norepinephrine in adrenergic nervous tissue, potentiate the pressor effects of indirectly acting sympathomimetic drugs such as pseudoephedrine. Infrequently, a hypertensive crisis may result. Pseudoephedrine should therefore be avoided in patients receiving drugs with MAO inhibiting activity, or for 2 weeks after discontinuance of an MAO inhibitor.108,109,110,111,112

Other Drugs

One manufacturer states that β-adrenergic blocking drugs such as propranolol also may increase the pressor effects of pseudoephedrine and that pseudoephedrine may reduce the antihypertensive effects of reserpine, methyldopa, mecamylamine hydrochloride, and veratrum alkaloids.

Pharmacology

Pseudoephedrine acts directly on both α- and, to a lesser degree, β-adrenergic receptors. It is believed that α-adrenergic effects result from the inhibition of the production of cyclic adenosine-3',5'-monophosphate (AMP) by inhibition of the enzyme adenyl cyclase, whereas β-adrenergic effects result from stimulation of adenyl cyclase activity. Like ephedrine, pseudoephedrine also has an indirect effect by releasing norepinephrine from its storage sites.

Pseudoephedrine acts directly on α-adrenergic receptors in the mucosa of the respiratory tract producing vasoconstriction that results in shrinkage of swollen nasal mucous membranes, reduction of tissue hyperemia, edema, and nasal congestion, and an increase in nasal airway patency; drainage of sinus secretions is increased. Sympathomimetic effects of pseudoephedrine presumably also may occur in other areas of the respiratory tract, including the eustachian tube; these effects may improve or maintain eustachian tube patency and allow equilibration of middle ear pressure during external atmospheric pressure changes (e.g., during descent of an aircraft, underwater diving, hyperbaric oxygenation).119,120,121

Pseudoephedrine may relax bronchial smooth muscle by stimulation of β₂-adrenergic receptors; however, substantial bronchodilation has not been demonstrated consistently following oral administration of the drug.

Oral administration of usual doses of pseudoephedrine to normotensive patients usually produces negligible effect on blood pressure. Pseudoephedrine may increase the irritability of the heart muscle and may alter the rhythmic function of the ventricles, especially in large doses or after administration to patients such as those with cardiac disease who are hypersensitive to the myocardial effects of sympathomimetic drugs. Tachycardia, palpitation, and/or multifocal premature ventricular contractions may occur. (See Cautions: Cardiovascular Effects.)

Pseudoephedrine may cause mild CNS stimulation, especially in patients who are sensitive to the effects of sympathomimetic drugs. (See Cautions: CNS Effects.)

Pharmacokinetics

Absorption

Pseudoephedrine is readily and almost completely absorbed from the GI tract and there is no evidence of first-pass metabolism.104 Following oral administration of a 60- or 120-mg dose of pseudoephedrine hydrochloride as an oral solution, peak plasma concentrations of about 180-300 or 397-422 ng/mL, respectively, were achieved in approximately 1.39-2 or 1.84-1.97 hours, respectively.104 Absorption from extended-release preparations is slower and peak plasma concentrations of the drug are achieved in about 3.8-6.1 hours.104 Following oral administration of single 30- or 60-mg doses of pseudoephedrine hydrochloride as a solution in pediatric patients (6-12 years of age), mean peak serum concentrations of 244 or 492 ng/mL, respectively, were achieved after 2.1 or 2.4 hours, respectively.103 Food delays absorption of the drug when administered as a solution, but appears not to have an effect on absorption when the drug is administered as extended-release preparations.104

Plasma pseudoephedrine concentrations of 274 ng/mL have been associated with a mean nasal decongestant response of 57.2%.104 After oral administration of 60 mg of pseudoephedrine hydrochloride as tablets or oral solution, nasal decongestion occurs within 30 minutes and persists for 4-6 hours. Nasal decongestion may persist for 8 hours following oral administration of 60 mg and up to 12 hours following 120 mg of the drug in extended-release capsules.

Distribution

Following oral administration of single 30- or 60-mg doses of pseudoephedrine hydrochloride as a solution in children (6-12 years of age), the mean apparent volume of distribution at steady-state was 2.6 or 2.4 L/kg, respectively.103

Although specific information is lacking, pseudoephedrine is presumed to cross the placenta and to enter CSF. Pseudoephedrine distributes into breast milk; about 0.5% of an oral dose is distributed into breast milk over 24 hours.104

Elimination

Pseudoephedrine is incompletely metabolized (less than 1%) in the liver by N -demethylation to an inactive metabolite. The drug and its metabolite are excreted in urine; 55-96% of a dose is excreted unchanged.

Urinary pH can affect the elimination half-life of pseudoephedrine, prolonging it when alkaline (pH 8) and reducing it when acidic (pH 5).16,103 The elimination half-life of pseudoephedrine ranges from 3-6 or 9-16 hours when urinary pH is 5 or 8, respectively, while when urinary pH is 5.8, the elimination half-life of the drug ranges from 5-8 hours.16,103 In one study in children 6-12 years of age, the elimination half-life of pseudoephedrine averaged about 3 hours when urinary pH was 6.5.16,103 The rate of urinary excretion of pseudoephedrine is accelerated when urine is acidified to a pH of about 5 by prior administration of ammonium chloride.16 When the urine is alkalinized to a pH of about 8 by prior administration of sodium bicarbonate, some of the drug is reabsorbed in the kidney tubule and the rate of urinary excretion is slowed.16

Renal clearance of pseudoephedrine is about 7.3-7.6 mL/minute per kg in adults.103,104 Following oral administration of a single 30- or 60-mg dose of pseudoephedrine hydrochloride given as an oral solution in children 6-12 years of age, total body clearance was faster than that reported in adults, averaging about 10.3 or 9.2 mL/minute per kg, respectively.103

Chemistry and Stability

Chemistry

Pseudoephedrine is a sympathomimetic drug that occurs naturally in plants of the genus Ephedra . The drug is a stereoisomer of ephedrine. Both naturally occurring pseudoephedrine and the official preparation are the dextrorotatory isomer. Pseudoephedrine is commercially available as the hydrochloride or sulfate salt.133 Pseudoephedrine hydrochloride is commercially available in single-ingredient preparations as well as in fixed-combination preparations; pseudoephedrine sulfate is commercially available in the US only in fixed-combination preparations. Pseudoephedrine hydrochloride and pseudoephedrine sulfate are available as fixed-combination preparations containing antihistamines, analgesics, antitussives, and/or expectorants. Pseudoephedrine hydrochloride occurs as fine, white to off-white crystals or powder having a faint, characteristic odor. The drug has solubilities of approximately 2 g/mL in water and 278 mg/mL in alcohol at 25°C. Pseudoephedrine sulfate occurs as a white, crystalline powder.

Stability

Pseudoephedrine hydrochloride preparations generally should be stored at 15-30°C; the oral solution should be protected from light,134 and freezing should be avoided. Pseudoephedrine hydrochloride tablets should be stored in tight containers and oral solution in tight, light-resistant containers.

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

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100. Public Law 104-237, 104th Cong., (3 October 1996), Comprehensive Methamphetamine Control Act of 1996 .

101. Maltz GA. Methamphetamine law will control bulk sales of “precursor chemicals”: earlier DEA ruling nullified. Pharmacy Today . 1996; 2:1,17.

102. Drug Enforcement Administration. Implementation of the Comprehensive Methamphetamine Control Act of 1996; regulation of pseudoephedrine, phenylpropanolamine, and combination ephedrine drug products and reports of certain transactions to nonregulated persons. 21 CFR Parts 1300, 1309, 1310. Proposed rule. [DEA No. 163P] Fed Regist . 1997; 62:52294-304.

103. Simons FER, Gu X, Watson WTA et al. Pharmacokinetics of the orally administered decongestants pseudoephedrine and phenylpropanolamine in children. J Pediatr . 1996; 129:729-34. [PubMed 8917241]

104. Kanfer I, Dowse R, Vuma V. Pharmacokinetics of oral decongestants. Pharmacotherapy . 1993; 13(6 Part 2):116S-28S. [PubMed 7507589]

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