Chlorpheniramine maleate

What it is

Chlorpheniramine maleate is a first-generation sedating antihistamine of the alkylamine (propylamine) class, sold as the maleate salt. In the United States it is an over-the-counter allergy medicine, typically a 4 mg tablet, and it is one of the two or three antihistamines most often found inside multi-ingredient cold and flu products. It blocks histamine H1 receptors and also blocks muscarinic acetylcholine receptors, which is where its drying and sedating effects come from. The molecule is a mixture of two mirror-image forms, and the more active one is cleared more slowly.

What the research says

For hay fever it does something modest, and the modern placebo-controlled evidence for it is surprisingly scanty for a drug this old. The most recent trial we could read gave 8 mg twice daily to 77 people over two weeks and found it beat placebo on the patients' own total symptom score but not on the investigators' score; it was funded by Pfizer. For chronic hives, the best trial we found used chlorpheniramine only as an open-label run-in and classed a third of patients as non-responders, so it gives no placebo-controlled estimate at all. For colds, Cochrane found antihistamine monotherapy had no clinically significant effect on individual symptoms, and for glue ear in children the pooled trials show no benefit and more side effects. The harm evidence is firmer than the benefit evidence: a single dose measurably lengthened the P300 evoked potential in school-age children without them noticing, the enantiomer dexchlorpheniramine measurably worsened on-the-road driving, first-generation antihistamines as a class are associated with about double the odds of injurious falls or fracture in older people, and chlorpheniramine clearance depends on CYP2D6, so exposure varies several-fold between people and rises sharply when that enzyme is blocked.

Evidence grade: Limited evidence.

How it works

Drug class: First-generation (sedating) H1-antihistamine, alkylamine (propylamine) class, with anticholinergic activity; maleate salt. Listed as an over-the-counter antihistamine active ingredient in the United States.

Chlorpheniramine competes with histamine at the H1 receptor in the lining of the nose, the airways and the skin, so the vasodilation, swelling, itch and mucus that histamine produces are reduced. It crosses into the brain, which is why it sedates, and it also blocks muscarinic acetylcholine receptors, which dries secretions and can blur vision, slow the bowel and make passing urine difficult. It is metabolised in the liver, partly by CYP2D6, and the two mirror-image forms of the molecule are handled differently: the more pharmacologically active one is cleared more slowly, with a half-life of around 18 hours in people with normal CYP2D6 activity. (Source 1)

What it is used for

• Chlorpheniramine maleate is a listed OTC antihistamine active ingredient at 4 mg every 4 to 6 hours. The most recent placebo-controlled trial we could read gave 8 mg twice daily and found it beat placebo on the patients' own total symptom score but not on the investigators' score; it was funded by Pfizer. Most of the rest of the efficacy base is decades old and predates modern reporting standards. Evidence: limited. (Source 2)
• Chlorpheniramine is widely used for hives and is not among the uses printed on the OTC allergy label. The best trial we found used it as an open-label run-in rather than against placebo, and classed 40 of 120 patients as non-responders after six weeks, so it gives no placebo-controlled estimate of chlorpheniramine's own effect. Evidence: limited. (Source 3)
• Cochrane found antihistamine monotherapy had no clinically significant effect on individual cold symptoms. Antihistamine-decongestant combinations did show a global benefit in adults with a number needed to treat of about four on moderate-certainty evidence, but at the cost of more adverse effects, and the review rated the overall data scarce and the symptom effect probably too small to be clinically relevant. Evidence: limited. (Source 4)
• Cochrane pooled 16 trials in 1880 children and found no statistical or clinical benefit for any outcome, with 11% more side effects in treated children and a number needed to harm of 9. The reviewers recommended against use. Evidence: not-supported. (Source 5)
• The Drug Facts label carries an explicit instruction not to use the product to make a child sleepy, and warns that excitability may occur in children instead. The objective evidence in children is that it does sedate, measured as lengthened P300 latency, without the child noticing. Evidence: not-supported. (Source 6)

Interactions

• Quinidine and other CYP2D6 inhibitors (pharmacokinetic study): Chlorpheniramine is cleared partly by CYP2D6. Blocking that enzyme with quinidine raised peak concentration of the active enantiomer, cut its clearance by more than half and stretched its half-life from about 18 to about 29 hours. (Source 7)
• Alcohol (label): The Drug Facts label tells people to avoid alcoholic beverages and names alcohol as something that increases the drowsiness, and the prescribing information for antihistamine-containing syrups describes the effect as additive. (Source 6)
• Sedatives, tranquillisers and other CNS depressants (label): Antihistamines add to the effect of sedatives, hypnotics, tranquillisers and anti-anxiety drugs. The OTC monograph requires a warning telling people not to take the product with sedatives or tranquillisers without consulting a doctor. Limit: This sentence appears in the prescribing information for a brompheniramine-containing syrup and is written about antihistamines as a class. We have used it as a class statement, not as chlorpheniramine-specific data. (Source 8)
• Other anticholinergic medicines (label): Dry mouth, blurred vision and constipation add up when chlorpheniramine is taken with other drugs that block acetylcholine. (Source 9)
• Monoamine oxidase inhibitors (label): MAO inhibitors are described in antihistamine prescribing information as prolonging and intensifying the drying anticholinergic effects of antihistamines. Limit: A class statement from a brompheniramine-containing product's label, applied here to chlorpheniramine as a member of the same class. We found no chlorpheniramine-specific MAO inhibitor interaction study. (Source 8)
• Grapefruit juice, St John's wort, melatonin, valerian and kava (theoretical): We found no clinical interaction study of chlorpheniramine with any of these. The nearest relevant evidence is that chlorpheniramine depends on CYP2D6, an enzyme grapefruit juice does not meaningfully inhibit, which is why the grapefruit interaction documented for many drugs is not documented for this one. Any added drowsiness from sedating supplements is theoretical for this drug. Limit: This is reasoning from the metabolic pathway, not a measured interaction. We searched PubMed for chlorpheniramine with grapefruit, St John's wort, melatonin, valerian and kava and found no clinical interaction study. (Source 10)

Stopping it

• We found no deprescribing or tapering trial for chlorpheniramine. The closest evidence on stopping concerns what happens while taking it: with the related enantiomer dexchlorpheniramine, the driving impairment seen on day one had gone by day eight of continuous dosing, which the authors read as tolerance. (Source 11)
• That tolerance is the reason the stopping question matters: in the same study the day-one impairment on the highway driving test had disappeared by day eight, so the drug's unwanted effect fades without the drug being stopped, and nothing in the literature we reached describes a withdrawal state when it is stopped. (Source 12)

What goes wrong

Adverse events were reported slightly more often on chlorpheniramine than on placebo in that trial, with somnolence and headache commonest. (Source 13)

• Randomized trial, Certainty not rated.
• Size: 310 participants in study 2.
• Who: People aged 12 and over with seasonal allergic rhinitis.
• How long: Two weeks.
• Result: 55% of chlorpheniramine subjects reported adverse events versus 51% on placebo, 43% on cetirizine 5 mg each morning and 46% on cetirizine 10 mg at bedtime.
• Funding: industry-funded.

Limit of this finding: The 4 percentage point difference from placebo is not tested for statistical significance in the text we read, and placebo itself produced adverse events in half the participants.

In study 2, 55% of subjects treated with chlorpheniramine reported AEs; 51%, 43%, and 46% of subjects receiving placebo, cetirizine 5-mg QAM, and cetirizine 10-mg QHS reported AEs.

In school-age children, a single dose of chlorpheniramine lengthened the P300 evoked potential, an objective marker of sedation, while placebo did not. (Source 14)

• Randomized trial, Certainty not rated.
• Size: 24 children aged 7 to 14 who completed the study.
• Who: Children aged 7 to 14 with perennial allergic rhinitis, Singapore.
• How long: Single doses in a three-way crossover, at least one week apart.
• Result: Both chlorpheniramine and cetirizine increased P300 latency from baseline; placebo produced no significant increase.
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

Chlorpheniramine and cetirizine increased P300 latency when compared with baseline. No significant increase was obtained with placebo.

That sedation was not something the children noticed. (Source 15)

• Randomized trial, Certainty not rated.
• Size: 24 children aged 7 to 14.
• Who: Children with perennial allergic rhinitis.
• How long: Single doses.
• Result: The increase in P300 latency was not accompanied by a significant change in subjective somnolence on a visual analogue scale.
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

Limit of this finding: The sentence we quote is from a conclusion that names cetirizine only, although the same paper's results section reports the lengthened P300 latency for chlorpheniramine as well as for cetirizine. Read alone it would suggest that only the newer drug was sedating, which is not what the trial found.

The lack of correlation between P300 latency and the visual analog scale indicates that sedation induced by these drugs may not be subjectively noted.

Dexchlorpheniramine, the active enantiomer of chlorpheniramine, measurably impaired on-the-road driving after a single dose. (Source 12)

• Randomized trial, Certainty not rated.
• Size: 16 healthy volunteers.
• Who: Healthy volunteers, Maastricht on-the-road highway driving test.
• How long: Four separate 8-day treatment periods, tested on days 1 and 8.
• Result: Dexchlorpheniramine Repetab 6 mg twice daily increased standard deviation of lateral position by 2 cm (95% CI 0.5, 3.8) on day 1.
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

Limit of this finding: The drug tested was dexchlorpheniramine, the dextrorotatory enantiomer, not racemic chlorpheniramine maleate. The pharmacology is closely related but this is not the same salt or the same molecule, and the dose is not interchangeable.

Dexchlorpheniramine and mequitazine significantly impaired driving performance on the highway driving test on the first day; dexchlorpheniramine increased Standard Deviation of Lateral Position by 2 cm [95% confidence interval (CI) 0.5, 3.8]

Volunteers did not anticipate the driving impairment before it happened. (Source 12)

• Randomized trial, Certainty not rated.
• Size: 16 healthy volunteers.
• Who: Healthy volunteers.
• How long: Single dose and 8 days.
• Result: Subjects knew their driving had been impaired after the day 1 test but had not expected it beforehand.
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

Although subjective ratings confirmed that subjects knew their driving had been impaired in the mequitazine and dexchlorpheniramine condition after completion of the highway driving test on day 1, they did not expect their driving to be affected before the start of the test.

Chlorpheniramine clearance depends on CYP2D6, and blocking that enzyme raised exposure and nearly doubled the half-life of the active enantiomer. (Source 7)

• Blood level study, Certainty not rated.
• Size: 8 healthy volunteers (6 extensive metabolisers, 2 poor metabolisers)
• Who: Healthy volunteers given a single 8 mg oral dose of racemic chlorpheniramine.
• How long: Single dose, with and without quinidine 50 mg every 6 hours.
• Result: For (S)-(+)-chlorpheniramine, quinidine raised Cmax to 13.94+/-1.51 ng/ml (P<0.01), cut oral clearance to 0.22+/-0.03 l/h/kg (P<0.01) and extended half-life from 18.0+/-2.0 h to 29.3+/-2.0 h (P<0.001)
• Funding: Research Support, U.S. Gov't, P.H.S. per the PubMed record.

Limit of this finding: Only two poor metabolisers were studied, so the poor-metaboliser comparison rests on two people. The abstract also prints the raised Cmax as '13.94+/-1.51' with no unit, although the figures before it are in ng ml-1; we have left the number as the paper prints it rather than supply a unit the paper does not state.

For (S)-(+)-chlorpheniramine, administration of quinidine, an inhibitor of CYP2D6, resulted in an increase in Cmax to 13.94+/-1.51 (P<0.01), a reduction in CLoral to 0.22+/-0.03 l h-1 kg-1 (P<0.01), and a prolongation of elimination half-life from 18.0+/-2.0 h to 29.3+/-2.0 h (P<0.001).

People who are CYP2D6 poor metabolisers had higher chlorpheniramine exposure from the same dose. (Source 7)

• Blood level study, Very low certainty.
• Size: 2 CYP2D6 poor metabolisers compared with 6 extensive metabolisers.
• Who: Healthy volunteers.
• How long: Single 8 mg oral dose.
• Result: Systemic exposure after chlorpheniramine alone was greater in poor metabolisers than in extensive metabolisers; quinidine then produced only a slight increase in oral clearance in poor metabolisers.
• Funding: Research Support, U.S. Gov't, P.H.S. per the PubMed record.

Limit of this finding: Two participants. This is a signal, not an estimate.

In CYP2D6 poor metabolizers, systemic exposure was greater after chlorpheniramine alone than in extensive metabolizers

Cochrane reported more adverse effects on antihistamine-decongestant combinations than on control, but its own odds ratio does not establish that difference. (Source 16)

• Systematic review, Moderate certainty.
• Size: 842 participants across the adverse-effect comparison (419 active, 423 control)
• Who: Adults and older children with the common cold.
• How long: Course of treatment, 3 to 10 days.
• Result: 128/419 (31%) on antihistamine-decongestant suffered one or more adverse effects versus 100/423 (13%) on control; OR 1.58, 95% CI 0.78 to 3.21.
• Funding: not stated in the abstract.

Limit of this finding: Two problems in the review itself. First, the confidence interval for the odds ratio (0.78 to 3.21) crosses 1, so the numbers do not support the directional sentence printed beside them. Second, the control-arm figure is misprinted: 100/423 is 23.6%, not the 13% the review states, so the true gap between the arms is about 7 percentage points rather than the 18 the printed percentages suggest. We quote the review as published and a reader should not take either the 13% or the directional wording at face value.

Adverse effects: the antihistamine-decongestant group experienced more adverse effects than the control group: 128/419 (31%) versus 100/423 (13%) participants suffered one or more adverse effects (OR 1.58, 95%CI 0.78 to 3.21; moderate certainty of evidence).

Cochrane found no benefit, and measurable harm, from antihistamines for otitis media with effusion in children. (Source 5)

• Systematic review, Certainty not rated.
• Size: 16 studies, 1880 participants.
• Who: Children presenting with otitis media with effusion.
• How long: Searches to 1 February 2011.
• Result: No statistical or clinical benefit for any intervention or outcome; treated subjects had 11% more side effects than untreated, number needed to harm 9.
• Funding: not stated in the abstract.

Limit of this finding: The '11% more side effects' is the review's own wording for an absolute difference of about 11 percentage points between treated and untreated children, which is what its number needed to harm of 9 corresponds to. It does not mean side effects were 11% more likely in relative terms.

No statistical or clinical benefit was found for any of the interventions or outcomes studied. However, treated study subjects experienced 11% more side effects than untreated subjects (number needed to treat to harm = 9).

First-generation antihistamines as a class were associated with roughly double the odds of injurious falls or fracture in older people. (Source 17)

• Meta-analysis, Low certainty.
• Size: Five observational studies from 473 screened.
• Who: Elderly patients.
• How long: Databases searched to November 2016.
• Result: OR 2.03, 95% CI 1.49-2.76, I2 = 0%.
• Funding: not stated in the abstract.

Limit of this finding: Class-level observational evidence. Chlorpheniramine is not separately identified in the abstract.

First-generation antihistamine use is considerably associated with an increased risk of injurious falls or fracture among the elderly.

Cumulative use of strong anticholinergics, a class in which first-generation antihistamines were one of the three commonest, tracked with incident dementia. (Source 18)

• Cohort study, Certainty not rated.
• Size: 3434 participants aged 65+; 797 developed dementia.
• Who: Older adults in an integrated health system in Seattle.
• How long: Mean follow-up 7.3 years.
• Result: Adjusted HR 1.54 (95% CI 1.21-1.96) for more than 1095 total standardized daily doses versus non-use.
• Funding: Research Support, N.I.H., Extramural per the PubMed record.

Limit of this finding: Observational, and the exposure is the whole anticholinergic class. It does not establish that chlorpheniramine causes dementia.

Higher cumulative anticholinergic use is associated with an increased risk for dementia.

Chlorpheniramine was embryolethal in animal reproduction studies at about nine times the maximum recommended human dose. (Source 19)

• Animal study, Certainty not rated.
• Size: Not stated in the label text.
• Who: Mice dosed throughout pregnancy, and male and female rats dosed before mating.
• How long: Throughout pregnancy, and pre-mating.
• Result: Embryolethal at approximately 9 times the maximum recommended human dose, with decreased postnatal survival when dosing continued after parturition.
• Funding: Not applicable - regulatory label.

Limit of this finding: Animal data at multiples of the human dose. It is not a human finding and does not establish human reproductive harm.

Chlorpheniramine administered by the oral route to mice throughout pregnancy was embryolethal at a dose approximately 9 times the MRHD and decreased postnatal survival when dosing was continued after parturition.

The over-the-counter label instructs that the drug must not be used to make a child sleepy, and that excitability may occur in children. (Source 6)

• Official position, Certainty not rated.
• Size: Not applicable - a label.
• Who: Children taking OTC chlorpheniramine.
• How long: Not applicable.
• Result: No rates are given on the Drug Facts label.
• Funding: Not applicable.

excitability may occur, especially in children

Anticholinergic side effects add up when chlorpheniramine is combined with other anticholinergic drugs. (Source 9)

• Official position, Certainty not rated.
• Size: Not applicable - a label.
• Who: Patients taking chlorpheniramine with other anticholinergics.
• How long: Not applicable.
• Result: No rates given.
• Funding: Not applicable.

Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with chlorpheniramine.

Chlorpheniramine is among the antihistamines named in the clinical literature on over-the-counter medicine misuse. (Source 20)

• Systematic review, Very low certainty.
• Size: 92 articles reviewed.
• Who: People misusing over-the-counter medicines.
• How long: Literature to the 2021 search.
• Result: No rates are reported; the designs were case reports, surveys and retrospective case series.
• Funding: not stated in the abstract.

Limit of this finding: The review names chlorpheniramine among the antihistamines examined but reports article counts only for dextromethorphan and diphenhydramine, so no chlorpheniramine-specific rate can be taken from it.

OTC drugs such as antihistamines, cough/cold medications, and decongestants are reportedly the most popular in being diverted and misused.

In the same trial, dry mouth and sore throat were reported more often by people on active treatment than by people on placebo. (Source 13)

• Randomized trial, Certainty not rated.
• Size: Study 1: 200 participants across four arms; study 2: 310 participants across four arms.
• Who: Adults and adolescents with seasonal allergic rhinitis.
• How long: 2 weeks.
• Result: No rates are given for these two events; the subsection reports only that they occurred occasionally and were more frequent on active treatment than on placebo.
• Funding: industry-funded.

Limit of this finding: The sentence groups every active arm together, so it does not separate chlorpheniramine from the cetirizine arms. The same subsection records that most adverse events were mild to moderate and that no serious adverse events were reported.

Dry mouth and pharyngitis occurred occasionally in each study and were reported more frequently in the active treatment groups compared with placebo.

What the evidence supports

Chlorpheniramine's clearance is stereoselective, with the more active enantiomer cleared more slowly. (Source 10)

• Blood level study, Certainty not rated.
• Size: 8 healthy volunteers.
• Who: Healthy volunteers.
• How long: Single 8 mg oral dose.
• Result: In extensive metabolisers mean Cmax was 12.55+/-1.51 ng/ml for (S)-(+)- versus 5.38+/-0.44 ng/ml for (R)-(-)-chlorpheniramine, and oral clearance 0.49+/-0.08 versus 1.07+/-0.15 l/h/kg (P<0.005)
• Funding: Research Support, U.S. Gov't, P.H.S. per the PubMed record.

Stereoselective elimination of chlorpheniramine occurs in humans, with the most pharmacologically active (S)-(+)-enantiomer cleared more slowly than the (R)-(-)-enantiomer.

Antihistamine-decongestant combinations for colds did produce a global benefit in adults, with a number needed to treat of about four, on moderate-certainty evidence. (Source 16)

• Systematic review, Moderate certainty.
• Size: 14 trials, 1298 participants; six pooled (281 active, 284 placebo)
• Who: Adults and older children with the common cold.
• How long: Final evaluation at 3 to 10 days.
• Result: Odds ratio of treatment failure 0.31 (95% CI 0.20 to 0.48), NNTB 3.9 (95% CI 3.03 to 5.2); 70% favourable response on active treatment versus 55% on placebo.
• Funding: not stated in the abstract.

Limit of this finding: The antihistamine in these combinations varied between trials and the benefit cannot be attributed to chlorpheniramine specifically. Cochrane also recorded that reporting of methods was generally poor. The review's own numbers are also not internally consistent here: an NNTB of 3.9 does not follow from the 70% against 55% response rates printed beside it, which imply a number nearer 7. We report both as the review prints them and a reader should not rely on the precision of either.

The odds ratio (OR) of treatment failure was 0.31 (95% confidence interval (CI) 0.20 to 0.48; moderate certainty evidence); number needed to treat for an additional beneficial outcome (NNTB) 3.9 (95% CI 3.03 to 5.2).

What the evidence does not support

The same trial's investigator-rated outcome did not separate any active treatment from placebo. (Source 2)

• Randomized trial, Certainty not rated.
• Size: 310 participants in study 2.
• Who: People aged 12 and over with seasonal allergic rhinitis.
• How long: Two weeks.
• Result: Investigator-assessed total symptom severity complex was numerically lower than placebo for the active groups but the difference was not statistically significant.
• Funding: industry-funded.

Investigator-assessed TSSC for the active treatment groups was numerically lower versus placebo (Figure 2(b)); however, this difference was not statistically significant.

Cochrane found that antihistamine monotherapy, chlorpheniramine among the drugs studied in this literature, gave no clinically significant relief of individual cold symptoms. (Source 4)

• Systematic review, Certainty not rated.
• Size: 18 RCTs, 4342 participants.
• Who: Adults and children with the common cold.
• How long: Up to ten days.
• Result: No clinically significant effect on nasal obstruction, rhinorrhoea or sneezing; no difference from placebo beyond day two.
• Funding: not stated in the abstract.

There is no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing.

Cochrane rated the overall data for antihistamine-containing cold combinations as scarce and the symptom effect as probably too small to matter. (Source 21)

• Systematic review, Low certainty.
• Size: 30 studies, 6304 participants.
• Who: Children and adults with the common cold.
• How long: Varied.
• Result: For the antihistamine-analgesic-decongestant comparison the global effect difference was less than one point on a four- or five-point scale; OR of treatment failure 0.47 (95% CI 0.33 to 0.67), NNTB 5.6.
• Funding: not stated in the abstract.

Based on these scarce data, the effect on individual symptoms is probably too small to be clinically relevant.

The OME reviewers recommended against using these drugs. (Source 22)

• Systematic review, Certainty not rated.
• Size: 16 studies, 1880 participants.
• Who: Children with otitis media with effusion.
• How long: Searches to February 2011.
• Result: Pooled data showed no benefit and some harm.
• Funding: not stated in the abstract.

The pooled data demonstrate no benefit and some harm from the use of antihistamines or decongestants alone or in combination in the management of OME

Where the evidence is mixed

In a randomised industry-funded trial, chlorpheniramine 8 mg twice daily beat placebo on the patients' own symptom scores but not on the investigators' scores. (Source 2)

• Randomized trial, Certainty not rated.
• Size: 77 participants on chlorpheniramine of 310 in study 2.
• Who: People aged 12 and over with seasonal allergic rhinitis during ragweed season, multicentre.
• How long: Two weeks.
• Result: Subject-assessed total symptom severity complex significantly lower than placebo (P <= .04); investigator-assessed score numerically lower but not statistically significant.
• Funding: industry-funded: the clinical studies were funded by Pfizer and publication support came from Johnson & Johnson Consumer Inc.

In study 2, the 2 cetirizine groups and the active comparator group had a significantly lower subject-assessed TSSC versus placebo

The trial was funded by one drug company and written up with medical-writing support paid for by another. (Source 23)

• Randomized trial, Certainty not rated.
• Size: Two trials, 511 participants in total.
• Who: People with seasonal allergic rhinitis.
• How long: Two weeks each.
• Result: Clinical studies funded by Pfizer; publication, analysis and editorial support funded by Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare.
• Funding: industry-funded.

The clinical studies were funded by Pfizer. Support for publication and analysis of the studies was provided by Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare. Editorial support was provided by Erin Scott, PhD, and Danielle Gross, PhD, from Complete Publication Solutions, LLC, which was funded by Johnson & Johnson Consumer Inc.

In chronic idiopathic urticaria, a third of patients did not respond to chlorpheniramine alone over six weeks, and in those non-responders adding cimetidine beat adding placebo. (Source 3)

• Randomized trial, Certainty not rated.
• Size: 120 patients entered; 40 H1 non-responders randomised (21 to cimetidine, 19 to placebo)
• Who: Patients with chronic idiopathic urticaria at five UK centres (Sheffield, London, Bristol, Cardiff, Leeds)
• How long: Six weeks of chlorpheniramine, then eight weeks of double-blind add-on.
• Result: Significant difference in favour of chlorpheniramine plus cimetidine at 4 weeks (P less than 0.05) and 8 weeks (P less than 0.01) on total symptom score; no significant treatment-related side effects noted.
• Funding: not stated.

Limit of this finding: This trial was not designed to test chlorpheniramine against placebo. Chlorpheniramine was the open-label run-in given to everyone, so it provides no placebo-controlled estimate of chlorpheniramine's own effect in urticaria, and 40 of 120 patients were classed as non-responders to it.

There was a statistically significant difference between the average response in the two treatment groups in favour of chlorpheniramine plus cimetidine after 4 and 8 weeks' treatment (P less than 0.05 and P less than 0.01, respectively).

The driving impairment wore off over eight days of continued dosing, which the authors attributed to tolerance. (Source 12)

• Randomized trial, Certainty not rated.
• Size: 16 healthy volunteers.
• Who: Healthy volunteers.
• How long: 8 days.
• Result: The day 1 impairment on the highway driving test had disappeared by day 8.
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

These effects on driving performance disappeared after 8 days of treatment.

Where the research disagrees

Whether chlorpheniramine beats placebo for seasonal allergic rhinitis

• Urdaneta and colleagues, two randomised double-blind trials, 2018, subject-rated outcome, randomised, double-blind, parallel-group multicentre trial, subject-assessed total symptom severity complex: In study 2, the 2 cetirizine groups and the active comparator group had a significantly lower subject-assessed TSSC versus placebo (Source 2)
• The same trial, investigator-rated outcome, the same randomised trial, investigator-assessed total symptom severity complex: Investigator-assessed TSSC for the active treatment groups was numerically lower versus placebo (Figure 2(b)); however, this difference was not statistically significant. (Source 2)

Whether first-generation antihistamines are inferior to second-generation ones for allergic rhinitis symptom relief

• Simons and Simons, narrative review of a century of H1-antihistamines, 2011, narrative review with no stated search method: Unlike first (old)-generation H(1)-antihistamines introduced from 1942 to the mid-1980s, most of the second (new)-generation H(1)-antihistamines introduced subsequently have been investigated extensively with regard to clinical pharmacology, efficacy, and safety; moreover, they are relatively free from adverse effects and not causally linked with fatalities after overdose. (Source 24)
• Klein and colleagues, randomised placebo-controlled multicentre trial of the related alkylamine brompheniramine, 1996, randomised, double-blind, placebo-controlled multicentre parallel trial: At all post-baseline evaluations (days 3, 7, and 14), brompheniramine was significantly better (P < or = .05) than terfenadine and placebo for both sets of summed symptom scores and for both global assessments. (Source 25)

How much

• Reference intake: There is no reference intake, because this is a medicine and not a nutrient. How much a person takes is set by the product label or by a prescriber. As a position, the US over-the-counter antihistamine monograph, in the Code of Federal Regulations edition revised as of 1 April 2025, directs 4 mg every 4 to 6 hours for adults and children 12 and over, 2 mg every 4 to 6 hours for children 6 to under 12, and a doctor to be consulted for children under 6. (Source 26)
• Upper limit: There is no toxicological upper limit of the kind set for nutrients. The regulatory ceiling, as a position of the US Food and Drug Administration recorded in the Code of Federal Regulations edition revised as of 1 April 2025, is 24 mg in 24 hours for adults and children 12 and over, and 12 mg in 24 hours for children 6 to under 12. (Source 26)
• Studied: The pharmacokinetic study of CYP2D6 gave a single 8 mg oral dose of racemic chlorpheniramine to eight healthy volunteers, with and without quinidine 50 mg every 6 hours. (Source 7)
• Studied: The most recent allergic rhinitis trial we could read gave chlorpheniramine 8 mg twice daily for two weeks to 77 participants with ragweed-season seasonal allergic rhinitis, against cetirizine and placebo. (Source 13)
• Studied: The paediatric sedation study gave a single dose to 24 children aged 7 to 14 with perennial allergic rhinitis in a three-way crossover against cetirizine and placebo, measuring the P300 evoked potential. (Source 14)
• Studied: The chronic urticaria trial gave therapeutic doses of chlorpheniramine for six weeks to 120 patients as an open run-in, then randomised the 40 non-responders to added cimetidine 400 mg four times daily or placebo for eight weeks. (Source 3)

A common belief, and what the research shows

The belief: Chlorpheniramine is a mild, old, well-understood drug, and because it can be bought off a shelf for a few pence it must be among the best-evidenced antihistamines there is.

What the research shows: Age is not the same as evidence. The most recent placebo-controlled trial we could read found the benefit on the patients' own score but not on the investigators': 'Investigator-assessed TSSC for the active treatment groups was numerically lower versus placebo (Figure 2(b)); however, this difference was not statistically significant.' In children the sedation it causes is real and unnoticed: a single dose lengthened the P300 evoked potential, and 'The lack of correlation between P300 latency and the visual analog scale indicates that sedation induced by these drugs may not be subjectively noted.' In older adults the class carries measured risk, not theoretical risk: 'First-generation antihistamine use is considerably associated with an increased risk of injurious falls or fracture among the elderly.' And the dose that reaches the bloodstream is not the same in everyone, because 'CYP2D6 plays a role in the metabolism of chlorpheniramine in humans.'

Questions and answers

What is it?

Chlorpheniramine maleate is a first-generation sedating antihistamine of the alkylamine class, sold as the maleate salt. In the United States it is an over-the-counter allergy medicine, usually a 4 mg tablet, and it is also one of the commonest antihistamines inside multi-ingredient cold and flu products. It blocks histamine H1 receptors and also blocks acetylcholine receptors, which gives it drying and sedating effects. (Source 1)

What does it do in the body?

It stops histamine acting at the H1 receptor, so the swelling, leakiness and mucus that histamine causes in the lining of the nose and airways are reduced. Because it crosses into the brain it also sedates, and because it blocks acetylcholine receptors it dries secretions and can cause blurred vision and constipation. Its clearance depends partly on the liver enzyme CYP2D6, so exposure varies between people. (Source 1)

Is it good or bad for you?

Both, depending on who is taking it and why. For hay fever it has a real but modest effect that in the most recent trial we read showed up on the patients' scores and not the investigators'. Against that sits the harm side: it sedates children measurably without their noticing, the enantiomer impairs driving, and in older people the class is associated with about double the odds of injurious falls or fracture. (Source 17)

How do you get more of it?

It is a medicine, not a nutrient, so there is no reason to seek more of it. It is sold without prescription and the US OTC monograph sets the permitted amount at 4 mg every four to six hours with a ceiling of 24 mg a day for adults and children 12 and over, and half that for children aged 6 to under 12. That is the regulator's position, not advice, and how much anyone takes is a matter for a prescriber or pharmacist. (Source 26)

If it is harmful, what reduces it?

Its effect wears off on its own, and some of its unwanted effects fade even while it is being taken. In a driving study of the closely related dexchlorpheniramine, impairment present on day one had gone by day eight of continuous dosing. Reducing the anticholinergic burden it contributes means stopping or substituting it, which is a clinical decision rather than something to do from a label. (Source 11)

Why might someone be low in it or missing it?

Does not apply. Chlorpheniramine maleate is a manufactured medicine, not a substance the body makes or needs, so no one can be deficient in it. The regulatory record treats it purely as a listed active ingredient with a set dose. (Source 26)

We searched: We searched PubMed and Europe PMC for chlorpheniramine deficiency and endogenous chlorpheniramine and found nothing, as expected for a synthetic drug.

Which whole foods contain it or feed it?

Does not apply. No whole food contains chlorpheniramine maleate; it reaches people only as a manufactured medicine, listed in US regulation as an OTC antihistamine active ingredient with a defined dose. (Source 26)

We searched: We searched PubMed and Europe PMC for dietary and natural food sources of chlorpheniramine and found no reports of natural occurrence.

What happens if you do not have it?

Nothing happens that matters to health, because the body does not need it. Not taking it for a cold means forgoing an effect Cochrane judged clinically insignificant for nasal blockage, runny nose and sneezing; for glue ear in children, not taking it means avoiding a measurable excess of side effects for no benefit. (Source 4)

How can you test for it?

There is no routine clinical test and no reason to have one. Blood concentrations are measured in pharmacokinetic research, where they show that clearance depends on the CYP2D6 enzyme and differs between the two mirror-image forms of the molecule. CYP2D6 genotyping exists as a pharmacogenetic test and explains part of the variation in exposure between people, but it is not used to guide chlorpheniramine dosing and we found no validated monitoring test. (Source 10)

We searched: We searched PubMed for chlorpheniramine therapeutic drug monitoring, plasma concentration assay and CYP2D6-guided dosing; we found pharmacokinetic studies but no validated clinical test or dosing algorithm.

References

1. DailyMed, US National Library of Medicine. TUXARIN ER (codeine phosphate and chlorpheniramine maleate) extended-release tablet - prescribing information, MainPointe Pharmaceuticals, SPL version 6, published 19 January 2024 (the SPL's own effectiveTime is 10 January 2024): the Chlorpheniramine subsection of section 12.1 Mechanism of Action. 2024. Read the source
2. Allergy & rhinology (Providence, R.I.). Assessment of Different Cetirizine Dosing Strategies on Seasonal Allergic Rhinitis Symptoms: Findings of Two Randomized Trials - TSSC Over 2 Weeks results passage. 2018. PMID 30027003, DOI 10.1177/2152656718783630. Read the source
3. The British journal of dermatology. Cimetidine and chlorpheniramine in the treatment of chronic idiopathic urticaria: a multi-centre randomized double-blind study. 1987. PMID 3307890, DOI 10.1111/j.1365-2133.1987.tb04095.x. Read the source
4. The Cochrane database of systematic reviews. Antihistamines for the common cold - AUTHORS' CONCLUSIONS section of the abstract. 2015. PMID 26615034, DOI 10.1002/14651858.CD009345.pub2. Read the source
5. The Cochrane database of systematic reviews. Antihistamines and/or decongestants for otitis media with effusion (OME) in children - MAIN RESULTS section of the abstract. 2011. PMID 21901683, DOI 10.1002/14651858.CD003423.pub3. Read the source
6. DailyMed, US National Library of Medicine. ALLERGY RELIEF (chlorpheniramine maleate) tablet - Drug Facts label, Walgreen Company, published 2 October 2026. 2026. Read the source
7. British journal of clinical pharmacology. The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine - RESULTS section of the abstract. 2002. PMID 11994058, DOI 10.1046/j.1365-2125.2002.01578.x. Read the source
8. DailyMed, US National Library of Medicine. Brompheniramine Maleate, Pseudoephedrine Hydrochloride and Dextromethorphan Hydrobromide Oral Syrup - prescribing information, Padagis US LLC, published 22 July 2026: Drug Interactions subsection of PRECAUTIONS. 2026. Read the source
9. DailyMed, US National Library of Medicine. TUXARIN ER (codeine phosphate and chlorpheniramine maleate) extended-release tablet - prescribing information, MainPointe Pharmaceuticals, SPL version 6, published 19 January 2024 (the SPL's own effectiveTime is 10 January 2024): section 7.10 Anticholinergic Drugs. 2024. Read the source
10. British journal of clinical pharmacology. The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine - CONCLUSIONS section of the abstract. 2002. PMID 11994058, DOI 10.1046/j.1365-2125.2002.01578.x. Read the source
11. British journal of clinical pharmacology. Repeated-dose effects of mequitazine, cetirizine and dexchlorpheniramine on driving and psychomotor performance - CONCLUSIONS section of the abstract. 2006. PMID 16390354, DOI 10.1111/j.1365-2125.2005.02524.x. Read the source
12. British journal of clinical pharmacology. Repeated-dose effects of mequitazine, cetirizine and dexchlorpheniramine on driving and psychomotor performance - RESULTS section of the abstract. 2006. PMID 16390354, DOI 10.1111/j.1365-2125.2005.02524.x. Read the source
13. Allergy & rhinology (Providence, R.I.). Assessment of Different Cetirizine Dosing Strategies on Seasonal Allergic Rhinitis Symptoms: Findings of Two Randomized Trials - Safety results passage. 2018. PMID 30027003, DOI 10.1177/2152656718783630. Read the source
14. Pediatrics. Central nervous system side effects of first- and second-generation antihistamines in school children with perennial allergic rhinitis: a randomized, double-blind, placebo-controlled comparative study - RESULTS section of the abstract. 2004. PMID 14754980, DOI 10.1542/peds.113.2.e116. Read the source
15. Pediatrics. Central nervous system side effects of first- and second-generation antihistamines in school children with perennial allergic rhinitis: a randomized, double-blind, placebo-controlled comparative study - CONCLUSION section of the abstract. 2004. PMID 14754980, DOI 10.1542/peds.113.2.e116. Read the source
16. The Cochrane database of systematic reviews. Oral antihistamine-decongestant-analgesic combinations for the common cold - MAIN RESULTS section of the abstract. 2022. PMID 35060618, DOI 10.1002/14651858.CD004976.pub4. Read the source
17. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. Antihistamine use and the risk of injurious falls or fracture in elderly patients: a systematic review and meta-analysis - UNLABELLED summary section of the abstract. 2018. PMID 30046925, DOI 10.1007/s00198-018-4564-z. Read the source
18. JAMA internal medicine. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study - CONCLUSIONS AND RELEVANCE section of the abstract. 2015. PMID 25621434, DOI 10.1001/jamainternmed.2014.7663. Read the source
19. DailyMed, US National Library of Medicine. TUXARIN ER (codeine phosphate and chlorpheniramine maleate) extended-release tablet - prescribing information, MainPointe Pharmaceuticals, SPL version 6, published 19 January 2024 (the SPL's own effectiveTime is 10 January 2024): section 8.1 Pregnancy, Risk Summary. 2024. Read the source
20. Frontiers in psychiatry. Focus on Over-the-Counter Drugs' Misuse: A Systematic Review on Antihistamines, Cough Medicines, and Decongestants. 2021. PMID 34025478, DOI 10.3389/fpsyt.2021.657397. Read the source
21. The Cochrane database of systematic reviews. Oral antihistamine-decongestant-analgesic combinations for the common cold - AUTHORS' CONCLUSIONS section of the abstract. 2022. PMID 35060618, DOI 10.1002/14651858.CD004976.pub4. Read the source
22. The Cochrane database of systematic reviews. Antihistamines and/or decongestants for otitis media with effusion (OME) in children - AUTHORS' CONCLUSIONS section of the abstract. 2011. PMID 21901683, DOI 10.1002/14651858.CD003423.pub3. Read the source
23. Allergy & rhinology (Providence, R.I.). Assessment of Different Cetirizine Dosing Strategies on Seasonal Allergic Rhinitis Symptoms: Findings of Two Randomized Trials - Funding statement. 2018. PMID 30027003, DOI 10.1177/2152656718783630. Read the source
24. The Journal of allergy and clinical immunology. Histamine and H1-antihistamines: celebrating a century of progress. 2011. PMID 22035879, DOI 10.1016/j.jaci.2011.09.005. Read the source
25. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. Brompheniramine, terfenadine, and placebo in allergic rhinitis - RESULTS section of the abstract. 1996. PMID 8933774, DOI 10.1016/S1081-1206(10)63334-0. Read the source
26. Office of the Federal Register, National Archives and Records Administration. 21 CFR 341.72(d) Directions - oral dosage limits for every antihistamine active ingredient listed for OTC antihistamine drug products, subparagraphs (1) to (13), including brompheniramine maleate, chlorpheniramine maleate, diphenhydramine citrate and diphenhydramine hydrochloride (CFR edition revised as of 1 April 2025). 2025. Read the source