AHFS Class:

• First Generation Antihistamines 4:04

Generic Name(s):

• Chlorpheniramine Maleate

• Dexchlorpheniramine Maleate

Associated Monographs

• Antihistamines General Statement

Chlorpheniramine is an alkylamine (propylamine)-derivative, first generation antihistamine.

Administration

Chlorpheniramine maleate and dexchlorpheniramine maleate are administered orally.

Dosage

Dosage of chlorpheniramine and dexchlorpheniramine should be individualized according to the patient's response and tolerance. Dosage of dexchlorpheniramine maleate is approximately 50% that of chlorpheniramine maleate.

Chlorpheniramine Maleate

For self-medication of allergic rhinitis in adults and children 12 years of age and older, the usual oral dosage of chlorpheniramine maleate alone or in fixed-combination preparations is 4 mg every 4-6 hours, not to exceed 24 mg in 24 hours. Alternatively, for self-medication, adults and children 12 years of age and older may receive an extended-release formulation containing 8 or 12 mg of the drug twice daily in the morning and evening, not to exceed 24 mg in 24 hours. The usual oral dosage of chlorpheniramine maleate alone or in fixed-combination preparations for self-medication in children 6 to younger than 12 years of age is 2 mg every 4-6 hours, not to exceed 12 mg in 24 hours. (See Cautions: Pediatric Precautions.) Under the direction of a clinician, children 2 to younger than 6 years of age may receive 1 mg every 4-6 hours, not to exceed 6 mg in 24 hours. Under the direction of a clinician, children 6 to younger than 12 years of age may be given an extended-release formulation containing 8 mg of the drug once daily at bedtime or during the day, as indicated. For fixed-combination preparations, lower maximum daily chlorpheniramine maleate dosages may be necessary because of other ingredients (e.g., acetaminophen, pseudoephedrine hydrochloride) included in the formulations.

Dexchlorpheniramine Maleate

For self-medication of allergic rhinitis in adults and children 12 years of age and older, the usual oral dosage of dexchlorpheniramine maleate is 2 mg every 4-6 hours, not to exceed 12 mg in 24 hours. The usual oral dosage of the drug for self-medication in children 6 to younger than 12 years of age is 1 mg every 4-6 hours, not to exceed 6 mg in 24 hours. Under the direction of a clinician, children 2 to younger than 6 years of age may receive 0.5 mg every 4-6 hours, not to exceed 3 mg in 24 hours.

Chlorpheniramine and dexchlorpheniramine share the toxic potentials of other antihistamines, and the usual precautions of antihistamine therapy should be observed. (See Cautions in the Antihistamines General Statement 4:00.)

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 some commercially available preparations may contain aspartame (e.g., NutraSweet^®) which is metabolized in the GI tract to phenylalanine following oral administration. Some commercially available preparations also may contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.

Pediatric Precautions

Like other antihistamines, chlorpheniramine and dexchlorpheniramine should not be used in premature or full-term neonates. (See Cautions: CNS Effects and Pediatric Precautions, in the Antihistamines General Statement 4:00.) Conventional chlorpheniramine preparations and extended-release preparations of the drug should be used in children younger than 6 years of age and in those younger than 12 years of age, respectively, only under the direction and supervision of a physician. Safety and efficacy of dexchlorpheniramine in children younger than 2 years of age have not been established.

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. 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]) for the symptomatic treatment of cold and cough have not been established. Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of a the agency continues to assess safety and efficacy of these preparations in older children. Meanwhile, because children 2-3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age. FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in the Antihistamines General Statement 4:00.

Mutagenicity and Carcinogenicity

The mutagenic and carcinogenic potentials of dexchlorpheniramine have not been determined. No evidence of chlorpheniramine-induced mutagenesis was seen in the Ames microbial mutagen test or mouse lymphoma cells, with or without metabolic activation, nor in Chinese hamster ovary cells with metabolic activation; however, a weak but reproducible increase in sister chromatid exchanges occurred in Chinese hamster ovary cells in the absence of metabolic activation. No evidence of carcinogenesis was seen in a 24-month study in mice or rats receiving oral chlorpheniramine maleate dosages up to 200 or 60 mg/kg daily, respectively, although a proliferative effect, evidenced by an increased incidence of thyroid gland follicular cell hyperplasia, cysts, and adenomas, was observed in female mice.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in animals using dexchlorpheniramine have not been performed to date, but reproduction studies in rabbits and rats using chlorpheniramine maleate dosages up to 50 and 85 times the usual human dosage, respectively, have not revealed evidence of harm to the fetus. Decreased postnatal survival in offspring of rats receiving 33 and 67 times the usual human dosage of chlorpheniramine maleate has been reported. There are no adequate and controlled studies to date using chlorpheniramine or dexchlorpheniramine in pregnant women, and the drugs should be used during the first 2 trimesters only when clearly needed. In one epidemiologic study, use of chlorpheniramine was not associated with an increased risk of teratogenic effects; however, only a limited number of pregnant women received the drug in this study. Because of the risk of severe reactions (e.g., seizures) to antihistamines in neonates, chlorpheniramine or dexchlorpheniramine should not be used during the third trimester.

Fertility

Impaired fertility has been reported in female rats receiving chlorpheniramine maleate dosages approximately 67 times the usual human dosa however, more recent studies in rabbits and rats using more appropriate methodology and dosages up to 50 and 85 times the usual human dosage, respectively, have not revealed evidence of impaired fertility.

Lactation

It is not known whether chlorpheniramine or dexchlorpheniramine is distributed into milk, but other antihistamines (e.g., diphenhydramine) have been detected in milk. Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or chlorpheniramine or dexchlorpheniramine, taking into account the importance of the drug to the woman.

Pharmacokinetics

Absorption

Chlorpheniramine maleate appears to be well absorbed following oral administration; however, the drug undergoes substantial metabolism in the GI mucosa during absorption and on first pass through the liver. Limited data indicate that about 25-45% and 35-60% of a single oral dose of chlorpheniramine maleate as conventional tablets or a solution, respectively, reaches the systemic circulation as unchanged drug. Limited data also indicate that the bioavailability of extended-release preparations of the drug is reduced compared with that of conventional tablets or oral solution.

Following oral administration as conventional tablets or a solution of the maleate, chlorpheniramine appears in plasma within 30-60 minutes and peak plasma concentrations of the drug generally occur within 2-6 hours. Following oral administration of a single 4-mg dose of the drug as conventional tablets or a solution in fasting, healthy adults, mean peak plasma chlorpheniramine concentrations of 11 and 5.9 ng/mL, respectively, have been reported. Following oral administration of a single 0.12-mg/kg dose as a solution in fasting children with allergic rhinitis, peak plasma drug concentrations ranged from 8-18.5 ng/mL. The antihistamine effect, as determined by suppression of the wheal and flare responses induced by intradermal administration of histamine, is apparent within 6 hours after a single oral dose of the drug and may persist for up to at least 24 hours.

Distribution

Distribution of chlorpheniramine into human body tissues and fluids has not been characterized fully. Following IV administration in rabbits, highest concentrations of the drug are attained in the lungs, heart, kidneys, brain, small intestine, and spleen, with lower concentrations in the large intestine, muscle, stomach, adrenals, fat, liver, and mesentery.

Following IV administration in humans, chlorpheniramine undergoes rapid and extensive distribution. The apparent steady-state volume of distribution of the drug following IV administration reportedly averages 2.5-3.2 L/kg in adults and 3.8 L/kg in children. Chlorpheniramine is distributed into saliva, and the drug and/or its metabolites appear to be distributed in small amounts into bile.

In vitro, chlorpheniramine is approximately 69-72% bound to plasma proteins.

Elimination

Following IV administration of chlorpheniramine maleate, plasma concentrations of the drug have generally been reported to decline in a biphasic manner; however, one report indicates that the drug may exhibit triphasic elimination with a very rapid initial distribution phase. In adults with normal renal and hepatic function, the terminal elimination half-life of chlorpheniramine reportedly ranges from 12-43 hours; although early studies suggested a half-life of 2-4 hours, these values may have resulted from short sampling times and differences in the assays employed. In children with normal renal and hepatic function, the terminal elimination half-life reportedly averages 9.6-13.1 hours (range: 5.2-23.1 hours). In some patients with chronic renal failure undergoing hemodialysis, the elimination half-life of chlorpheniramine reportedly ranged from 280-330 hours.

Chlorpheniramine is rapidly and extensively metabolized, and undergoes substantial metabolism in the GI mucosa during absorption and on first pass through the liver following oral administration. Chlorpheniramine undergoes N -dealkylation to form monodesmethylchlorpheniramine and didesmethylchlorpheniramine, but is principally metabolized to other (at least 2) unidentified metabolites. Chlorpheniramine and its metabolites are apparently excreted almost completely in urine. Urinary excretion of chlorpheniramine and its N -dealkylated metabolites varies with urinary pH and urine flow, decreasing substantially as urinary pH increases and urine flow decreases. Following a single oral or IV dose of chlorpheniramine maleate in healthy individuals with normal renal and hepatic function in one study, about 20% of the dose was excreted in urine within 24 hours and 35% within 48 hours, and less than 1% was excreted in feces within 48 hours; about 3-7% of the dose was excreted in urine as unchanged drug within 48 hours, 2-4% as monodesmethylchlorpheniramine, 1-2% as didesmethylchlorpheniramine, and the remainder as unidentified metabolites. In other studies in healthy individuals with normal renal and hepatic function, about 20% of a single oral dose was excreted in urine as unchanged drug, 20% as monodesmethylchlorpheniramine, and 5% as didesmethylchlorpheniramine.

Chemistry and Stability

Chemistry

Chlorpheniramine is an alkylamine (propylamine)-derivative antihistamine. Chlorpheniramine differs from brompheniramine in the substitution of a chlorine atom for the bromine atom of the latter compound. Dexchlorpheniramine, the dextro isomer, is approximately twice as active as racemic chlorpheniramine on a weight basis. Chlorpheniramine maleate and dexchlorpheniramine maleate occur as white, odorless, crystalline powders. Chlorpheniramine maleate has solubilities of approximately 250 mg/mL in water and 100 mg/mL in alcohol at 25°C. Dexchlorpheniramine maleate has solubilities of approximately 0.9 g/mL in water and 0.5 g/mL in alcohol at 25°C. The pK_a of chlorpheniramine is approximately 9.2.

Stability

Chlorpheniramine maleate and dexchlorpheniramine maleate preparations generally should be stored at a temperature less than 40°C, preferably at 15-30°C. Chlorpheniramine maleate oral solution and dexchlorpheniramine maleate oral solution should be stored in tight, light-resistant containers and chlorpheniramine maleate injection should be stored in light-resistant containers; freezing should be avoided. Chlorpheniramine maleate conventional or extended-release tablets should be stored in tight or well-closed containers.

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of chlorpheniramine and dexchlorpheniramine, see the Antihistamines General Statement 4:00.

Please see the general statement for a list of references.