Loratadine with pseudoephedrine

What it is

This is a fixed-dose combination of two unrelated medicines in one tablet. Loratadine is a second-generation antihistamine that blocks the H1 receptor without crossing readily into the brain, so it does not usually cause drowsiness. Pseudoephedrine is a sympathomimetic nasal decongestant that works by constricting blood vessels, which shrinks swollen nasal lining. In the 24-hour US product the tablet carries loratadine 10 mg in its coating and pseudoephedrine sulfate 240 mg in an extended-release core; the 12-hour product carries loratadine 5 mg and pseudoephedrine sulfate 120 mg.

What the research says

The combination is well supported for one thing: seasonal allergic rhinitis where blocked nose is part of the problem. Several placebo-controlled randomised trials, including one of 874 people, found it better than placebo and better than either component alone for the symptoms each component targets. For the common cold the evidence is thinner: a Cochrane review found antihistamine-decongestant combinations helped about 70% of adults against 55% on placebo, a number needed to treat of 3.9, but concluded the effect on individual symptoms is probably too small to be clinically relevant and found no evidence of effectiveness in young children. For glue ear in children the same class of combination was reviewed and recommended against. The side effects come almost entirely from the pseudoephedrine half: insomnia, dry mouth, nervousness, a small rise in blood pressure and heart rate, and rare reports of ischaemic colitis.

Evidence grade: Well established.

How it works

Drug class: Fixed-dose combination of a second-generation (non-sedating) H1-antihistamine with a sympathomimetic oral nasal decongestant

Two drugs doing two different jobs. The loratadine part is an antihistamine: it blocks the H1 histamine receptor, which is what drives sneezing, runny nose, itch and itchy watery eyes in an allergic reaction, and unlike older antihistamines it barely enters the brain. The pseudoephedrine part is a nasal decongestant: it constricts blood vessels, and that vasoconstriction reduces the swelling of the nasal lining that causes a blocked nose. The label states each ingredient's purpose plainly. (Source 1)

What it is used for

• In a randomised double-blind placebo-controlled trial of 874 people, the once-daily combination was consistently superior to placebo on total, total nasal and total nonnasal symptom scores (p < 0.01), beat pseudoephedrine alone for nonnasal symptoms and beat loratadine alone for nasal stuffiness. Two other placebo-controlled trials, one in 469 patients and one running 28 days, found the same direction of effect. Evidence: established. (Source 2)
• The OTC label lists this use. A Cochrane review of antihistamine-decongestant combinations found an odds ratio of treatment failure of 0.31 (95% CI 0.20 to 0.48) with 70% responding against 55% on placebo, number needed to treat 3.9, but the reviewers judged the effect on individual symptoms probably too small to be clinically relevant and found no evidence of effectiveness in young children. Evidence: limited. (Source 3)
• In a randomised placebo-controlled crossover study in 39 grass-sensitive patients in a pollen challenge chamber, a single dose of pseudoephedrine 60 mg was significantly more effective than placebo (P < .01) on nasal congestion over more than 6 hours, while phenylephrine 12 mg was not different from placebo (P = .56). Evidence: established. (Source 4)
• A Cochrane review of sixteen studies (1880 participants) found no statistical or clinical benefit for antihistamines, decongestants or the combination on any outcome studied, while treated children had 11% more side effects than untreated children, a number needed to harm of 9. The reviewers recommended against their use. Evidence: not-supported. (Source 5)
• This is an off-label use for the combination product, although loratadine alone is used for it. In a randomised double-blind trial of 192 patients, loratadine 10 mg once daily and emedastine were similar after 4 weeks: 54.5% of loratadine patients were symptom-free against 52.4% with emedastine, with mean change in total urticaria symptom score -5.67 with loratadine and -5.57 with emedastine. There was no placebo arm, so this shows equivalence to another antihistamine rather than benefit over nothing. Evidence: limited. (Source 6)

Interactions

• Monoamine oxidase inhibitors (MAOIs) (label): The label says not to use the product at all if you are taking a prescription MAOI, or within 2 weeks of stopping one. MAOIs block the breakdown of the kind of chemical messenger pseudoephedrine acts through, which can push blood pressure dangerously high. (Source 7)
• Alcohol (clinical trial): In a double-blind crossover trial with an on-the-road driving test, alcohol significantly affected almost every performance measure, while loratadine 10 mg had no significant effect on any performance parameter. Cetirizine's effects did look additive with alcohol; loratadine's did not, because there was no loratadine effect to add. This trial tested loratadine alone, not the combination with pseudoephedrine. (Source 8)
• Ketoconazole (a strong CYP3A4 inhibitor) (pharmacokinetic study): Ketoconazole raised loratadine blood levels by 307% and levels of its active metabolite by 73%, but the QTc interval on the electrocardiogram did not change significantly, and no other clinically relevant safety changes were seen. (Source 9)
• Cimetidine (an acid-reducing H2 blocker available over the counter) (pharmacokinetic study): Cimetidine raised loratadine blood levels by 103% without a meaningful change in the active metabolite (6% increase), and again without a significant change in QTc. (Source 9)
• Erythromycin (pharmacokinetic study): Erythromycin raised the area under the curve for loratadine by 40% and for its metabolite by 46%, with no difference between treatment groups in QTc interval and no reports of sedation or fainting. (Source 10)

Stopping it

• The label treats this as a short-course medicine and sets stopping rules rather than a taper: stop and ask a doctor if symptoms do not improve within 7 days or come with a fever, or if nervousness, dizziness or sleeplessness occurs. (Source 7)
• Adverse effects led a minority of people to stop in the trials rather than causing problems on withdrawal. In the 28-day placebo-controlled trial, 6% of patients in each group discontinued because of adverse experiences, and sedation occurred in 7% of each group, meaning the drop-out rate was no higher than on placebo. (Source 11)
• Where the harm is pseudoephedrine-driven vasoconstriction, stopping the drug was what resolved it: in the four-case ischaemic colitis series, all cases responded to abstinence from pseudoephedrine and medical supportive therapy, and none relapsed in the 8-12 months after discontinuing it. (Source 12)

What goes wrong

Insomnia and dry mouth were significantly more common on the combination than on placebo, and insomnia was far worse with the 12-hour than the 24-hour formulation. (Source 13)

• Randomized trial, Moderate certainty.
• Size: 469 patients.
• Who: patients with moderate-to-severe seasonal allergic rhinitis.
• How long: 2 weeks.
• Result: Insomnia 15% with the 12-hour tablet versus 4% with the 24-hour tablet and 2% with placebo (P < 0.01); dry mouth 13% with both active tablets versus 4% with placebo (P < 0.05)
• Funding: not stated in the abstract.

Insomnia was reported significantly more often (P < 0.01) in Claritin-D 12 Hour (15%) patients compared with Claritin-D 24 Hour (4%) and placebo (2%) patients. Dry mouth was reported significantly more often (P < 0.05) in Claritin-D 24 Hour (13%) and Claritin-D 12 Hour (13%) groups compared with placebo (4%).

Dry mouth, insomnia and nervousness were each reported by significantly more people on the combination than on placebo. (Source 11)

• Randomized trial, Low certainty.
• Size: Two hundred sixty-four patients.
• Who: patients with moderate to severe seasonal allergic rhinitis.
• How long: 28 days.
• Result: Dry mouth, insomnia and nervousness reported by a significantly greater proportion on active treatment (P less than or equal to .04); sedation in 7% of each group; 6% of each group discontinued for adverse experiences.
• Funding: not stated in the abstract.

Dry mouth, insomnia, and nervousness were reported by a significantly greater proportion (P less than or equal to .04) in the active-treatment group. Sedation occurred in 7% of patients in each treatment group and 6% of patients in each group discontinued the study because of adverse experiences.

Insomnia and nervousness tracked the pseudoephedrine component, not the antihistamine. (Source 2)

• Randomized trial, Moderate certainty.
• Size: 874 patients.
• Who: patients with moderate to severe seasonal allergic rhinitis.
• How long: 2 weeks.
• Result: Insomnia and nervousness were noted in a significantly greater number of patients treated with the combination or with pseudoephedrine (p <= 0.04) than with loratadine or placebo; all treatments were otherwise generally well tolerated with no serious or unusual adverse events.
• Funding: not stated in the abstract.

Insomnia and nervousness, adverse events commonly associated with pseudoephedrine, were noted in a significantly greater number of patients treated with SCH 434 QD or pseudoephedrine (p < or = 0.04) as compared with those treated with loratadine or placebo.

Oral pseudoephedrine produces a small but statistically significant rise in systolic blood pressure and heart rate, including in people with controlled hypertension. (Source 14)

• Meta-analysis, Moderate certainty.
• Size: Twenty-four trials with extractable vital sign information (45 treatment arms; 1285 patients)
• Who: adults in randomised placebo-controlled trials of oral pseudoephedrine, including a subgroup with controlled hypertension.
• How long: varies; shorter duration of use was associated with greater increases.
• Result: Systolic blood pressure +0.99 mm Hg (95% CI 0.08 to 1.90); heart rate +2.83 beats/min (95% CI 2.0 to 3.6); diastolic blood pressure not affected (+0.63 mm Hg, 95% CI -0.10 to 1.35); in controlled hypertension systolic +1.20 mm Hg (95% CI 0.56 to 1.84)
• Funding: not stated in the abstract.

Pseudoephedrine caused a small but significant increase in SBP (0.99, mm Hg; 95% CI, 0.08 to 1.90) and HR (2.83 beats/min; 95% CI, 2.0 to 3.6), with no effect on DBP (0.63 mm Hg, 95% CI, -0.10 to 1.35). The effect in patients with controlled hypertension demonstrated an SBP increase of similar magnitude (1.20 mm Hg; 95% CI, 0.56 to 1.84 mm Hg).

128 of 419 people taking an antihistamine-decongestant combination for a cold reported one or more adverse effects, against 100 of 423 on control, but the confidence interval around the pooled odds ratio spans no difference. (Source 15)

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

Limit of this finding: The source itself is inconsistent here, so the percentages should not be relied on. The review prints "100/423 (13%)", but 100 of 423 is 24%, not 13%; the other arm, 128 of 419 (31%), is correct. The review also says the combination group "experienced more adverse effects than the control group" while giving an odds ratio of 1.58 with a 95% confidence interval of 0.78 to 3.21, which includes 1 and therefore does not show a difference. Read this as "adverse effects were common in both groups and this analysis could not tell them apart", not as a demonstrated increase.

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).

Pseudoephedrine has been linked to ischaemic colitis, including in women with no vascular disease, with the colitis affecting the watershed area of the splenic flexure. (Source 16)

• Case series, Very low certainty.
• Size: four women aged 37 to 50 years.
• Who: women presenting with sudden colicky abdominal pain and rectal bleeding after daily pseudoephedrine use, three for about 1 week and one chronically for 6 months.
• How long: 1 week to 6 months of exposure.
• Result: All four had colitis on colonoscopy, primarily at the splenic flexure, with biopsies consistent with ischaemic injury; other causes of segmental colitis were excluded.
• Funding: not stated in the abstract.

On colonoscopy, all four patients had colitis, primarily affecting the splenic flexure in the anatomical watershed area. Other causes of segmental colitis, including infectious colitides, pseudomembranous colitis, and Crohn's disease, were not evident. Colonoscopic biopsies were consistent with ischemic injury.

In children with colds, somnolence was reported more often on pseudoephedrine than on placebo, while insomnia and nervousness were reported at similar rates in both groups. (Source 17)

• Randomized trial, Low certainty.
• Size: children aged 6 to 11 years in a multicenter randomised trial (group sizes not given in the abstract)
• Who: children aged 6 to 11 years with the common cold given pseudoephedrine hydrochloride 30 mg tablets or placebo.
• How long: up to 7 days of as-needed dosing.
• Result: Somnolence 71.9% on pseudoephedrine versus 63.9% on placebo; insomnia 34.4% versus 38.9%; nervousness 20.0% versus 23.6%.
• Funding: not stated in the abstract.

Somnolence was reported in a greater percentage of children on pseudoephedrine compared to placebo (71.9% vs 63.9%), while similar percentages of children in the same respective groups reported insomnia (34.4% and 38.9%) and nervousness (20.0% and 23.6%).

The label warns that several common conditions, and concurrent MAOI use, make this product unsafe or needing medical advice first. (Source 7)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: adults and children buying the product over the counter.
• How long: not applicable.
• Result: Do not use with a prescription MAOI or for 2 weeks after stopping one; ask a doctor first if you have heart disease, thyroid disease, high blood pressure, diabetes, prostate-related urinary trouble, or liver or kidney disease.
• Funding: manufacturer label (Bayer HealthCare LLC)

Ask a doctor before use if you have heart disease thyroid disease high blood pressure diabetes trouble urinating due to an enlarged prostate gland liver or kidney disease. Your doctor should determine if you need a different dose.

What the evidence supports

The once-daily loratadine-pseudoephedrine combination beat placebo on all three composite symptom scores in seasonal allergic rhinitis, and beat each of its own components on the symptoms that component targets. (Source 2)

• Randomized trial, Moderate certainty.
• Size: 874 patients.
• Who: patients with moderate to severe symptoms of seasonal allergic rhinitis.
• How long: 2 weeks.
• Result: Total, total nasal and total nonnasal symptom scores reduced significantly versus placebo (p < 0.01); superior to pseudoephedrine for nonnasal symptoms at all time points (p < 0.01) and superior to loratadine for nasal stuffiness at end point (p < 0.01); good or excellent physician-rated response in 58%.
• Funding: not stated in the abstract; the combination is the manufacturer's product SCH 434.

SCH 434 QD was consistently superior to placebo in controlling the symptoms of seasonal allergic rhinitis. Composite symptom scores (total, total nasal, and total nonnasal) were reduced significantly in patients treated with SCH 434 QD as compared with placebo (p < 0.01). When compared with its individual components, reductions in mean symptom scores were consistently greater, numerically, in patients treated with SCH 434 QD than in patients who were treated with either loratadine or pseudoephedrine alone. SCH 434 QD was superior to pseudoephedrine in reducing nonnasal symptoms at all time points (p < 0.01), and superior to loratadine in relieving nasal stuffiness at end point (p < 0.01).

Both the once-daily and the twice-daily combination tablets were superior to placebo for allergic rhinitis symptoms, with the once-daily form causing less insomnia. (Source 13)

• Randomized trial, Moderate certainty.
• Size: 469 patients.
• Who: patients with moderate-to-severe seasonal allergic rhinitis symptoms.
• How long: 2 weeks.
• Result: Both formulations consistently superior to placebo (P < 0.01) on total, nasal and nonnasal symptom scores, with significantly greater relief of rhinorrhoea and nasal stuffiness (P <= 0.05)
• Funding: not stated in the abstract.

Claritin-D 24 Hour and Claritin-D 12 Hour were consistently superior to placebo (P < 0.01) in reducing total, nasal, and nonnasal symptom scores. Patients in the Claritin-D 24 Hour and Claritin-D 12 Hour groups also had significantly greater (P </= 0.05) relief of rhinorrhea and nasal stuffiness as compared with placebo.

In a 28-day trial the combination beat placebo on combined nasal and non-nasal symptom scores and on the physician's overall rating. (Source 11)

• Randomized trial, Low certainty.
• Size: Two hundred sixty-four patients.
• Who: patients with moderate to severe seasonal allergic rhinitis in a multicenter study.
• How long: 28 days.
• Result: Significantly lower mean combined nasal and non-nasal symptom scores than placebo (P = .05); physician's rating of overall therapeutic response significantly better (P = .03)
• Funding: not stated in the abstract.

At the last evaluable visit, the active treatment group had significantly lower (P = .05) mean combined nasal and non-nasal symptom scores than the placebo group. Also, the physician's rating of overall therapeutic response was significantly better in the active-treatment group (P = .03).

A single dose of pseudoephedrine relieved nasal congestion better than placebo in an allergen challenge chamber, while phenylephrine did not. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 39 grass-sensitive patients.
• Who: patients with seasonal allergic rhinitis exposed to grass pollen in the Vienna Challenge Chamber.
• How long: single dose, measured over more than 6 hours.
• Result: Pseudoephedrine significantly more effective than both placebo (P < .01) and phenylephrine (P = .01); phenylephrine not significantly different from placebo on the primary endpoint (P = .56)
• Funding: not stated in the abstract.

Phenylephrine was not significantly different from placebo in the primary end point, mean change in nasal congestion score at more than 6 hours (P = .56), whereas pseudoephedrine was significantly more effective than both placebo (P < .01) and phenylephrine (P = .01).

Antihistamine-decongestant combinations give a measurable global benefit in colds, with a number needed to treat of 3.9. (Source 15)

• Systematic review, Moderate certainty.
• Size: 14 trials, 1298 participants; six studies were pooled, with 281 participants on active treatment and 284 on placebo.
• Who: children and adults with the common cold.
• How long: follow-up 3 to 10 days.
• Result: Odds ratio of treatment failure 0.31 (95% CI 0.20 to 0.48, moderate certainty); number needed to treat for an additional beneficial outcome 3.9 (95% CI 3.03 to 5.2); favourable response in 70% on active treatment against 55% on placebo.
• Funding: not stated in the abstract.

Limit of this finding: Two numbers in this Cochrane abstract do not add up, and one of them sits in the adverse-effects sentence rather than this benefit sentence. Where the review reports harms it prints "100/423 (13%)", but 100 of 423 is 24%. The benefit figures quoted here (odds ratio 0.31 and a number needed to treat of 3.9) are internally consistent; the authors' own conclusion is nonetheless that the effect on individual symptoms is probably too small to matter clinically.

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). On the final evaluation day (follow-up: 3 to 10 days), 55% of participants in the placebo group had a favourable response compared to 70% on active treatment.

Loratadine was as effective as emedastine for chronic idiopathic urticaria at 4 weeks, with fewer treatment-related adverse events. (Source 6)

• Randomized trial, Low certainty.
• Size: 192 patients.
• Who: patients with idiopathic chronic urticaria in a randomised, double-blind, multicentre European trial.
• How long: 4 weeks.
• Result: Symptom-free patients 54.5% with loratadine versus 52.4% with emedastine; mean change in total urticaria symptom score -5.67 +/- 3.26 with loratadine versus -5.57 +/- 3.15 with emedastine; adverse events in 17 loratadine patients (17.7%) versus twenty-three emedastine patients (23.9%), with 9 treatment-related events in 9 loratadine patients versus nineteen events in 15 emedastine patients (p = 0.0294)
• Funding: not stated in the abstract.

After 4 weeks of treatment the efficacy of the two drugs was similar in terms of mean change in total urticaria symptom score (- 5.57 +/- 3.15 with emedastine - 5.67 +/- 3.26 with loratadine), proportion of symptom-free patients (52.4% vs. 54.5%)

An expert review holds that pseudoephedrine's efficacy as a nasal decongestant is supported by clinical trials, while phenylephrine's is unproven. (Source 18)

• Expert review, not systematic, Low certainty.
• Size: not applicable; a literature search of electronic databases and textbooks.
• Who: people using over-the-counter oral nasal decongestants.
• How long: not applicable.
• Result: No pooled effect size is given; the review states that both drugs have a good safety record but that only pseudoephedrine's decongestant efficacy is supported by clinical trials, and that phenylephrine is extensively metabolized in the gut.
• Funding: not stated in the abstract.

PE is a poor substitute for PDE as an orally administered decongestant as it is extensively metabolized in the gut and its efficacy as a decongestant is unproven. Both PDE and PE have a good safety record, but the efficacy of PDE as a nasal decongestant is supported by clinical trials.

What the evidence does not support

The Cochrane reviewers concluded the effect on individual cold symptoms is probably too small to be clinically relevant, and that there is no evidence of effectiveness in young children. (Source 19)

• Systematic review, Low certainty.
• Size: all antihistamine-decongestant-analgesic trials included in the review.
• Who: children and adults with the common cold; children were included in nine trials.
• How long: varies by trial.
• Result: No pooled effect size is given for individual symptoms; the reviewers state the data are scarce and the effect probably too small to be clinically relevant, with no evidence of effectiveness in young children.
• 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 current evidence suggests that antihistamine-analgesic-decongestant combinations have some general benefit in adults and older children. These benefits must be weighed against the risk of adverse effects. There is no evidence of effectiveness in young children.

Antihistamines, decongestants and their combination gave no benefit at all for glue ear in children, and caused more side effects. (Source 5)

• Systematic review, Moderate certainty.
• Size: Sixteen studies (1880 participants)
• Who: children presenting with otitis media with effusion.
• How long: varies by trial.
• Result: No statistical or clinical benefit for any intervention or outcome studied; treated subjects experienced 11% more side effects than untreated subjects, number needed to treat to harm 9.
• Funding: not stated in the abstract.

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).

Neither pseudoephedrine nor phenylephrine had any effect on non-nasal allergy symptoms. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 39 grass-sensitive patients.
• Who: patients with seasonal allergic rhinitis in a pollen challenge chamber.
• How long: single dose over more than 6 hours.
• Result: Neither phenylephrine nor pseudoephedrine had an effect on the nonnasal symptoms; no adverse events were reported in the study.
• Funding: not stated in the abstract.

Neither phenylephrine nor pseudoephedrine had an effect on the nonnasal symptoms. No adverse events were reported in this study.

Loratadine 10 mg did not impair on-the-road driving or psychometric performance, unlike cetirizine in the same trial. (Source 8)

• Randomized trial, Moderate certainty.
• Size: Sixteen healthy male and female volunteers.
• Who: healthy volunteers in a 6-way double-blind crossover trial of cetirizine 10 mg, loratadine 10 mg and placebo, with and without alcohol.
• How long: single doses.
• Result: Loratadine had no significant effect on any performance parameter; cetirizine caused significantly greater variability in speed and lateral position and its effects appeared additive with alcohol.
• Funding: not stated in the abstract.

The effects of cetirizine of on driving performance resembled those of alcohol. It caused the subjects to operate with significantly greater variability in speed and lateral position ('weaving' motion). The effects of alcohol and cetirizine appeared to be additive. Certain cetirizine-placebo differences in subjective feelings and test battery performance were also significant. Loratadine had no significant effect on any performance parameter.

Across self-report, physiological and performance measures, loratadine 10 mg a day behaved like placebo on the central nervous system, in contrast to diphenhydramine. (Source 20)

• Expert review, not systematic, Low certainty.
• Size: not stated; a review of studies at the 10 mg daily dose.
• Who: people taking loratadine 10 mg per day in studies of cognition, psychomotor performance, mood and sedation.
• How long: not stated.
• Result: Effects on somnolence, fatigue and mood comparable to placebo; free of effects on EEG-evoked potentials and sleep latency tests; effects on driving, cognitive and psychomotor measures comparable to placebo, while diphenhydramine impaired vigilance, divided attention, working memory and psychomotor performance.
• Funding: not stated in the abstract.

Limit of this finding: This is a narrative review, not new data: the paper's own words are "This paper reviews of studies CNS functioning conducted with loratadine" (the ungrammatical sentence is the source's, left uncorrected). Its "comparable to placebo" statements are the reviewer's summary of other people's trials, with no stated search method and no pooled numbers, so they carry less weight than a systematic review of the same question.

Studies employing self-report measures, such as diary cards, visual analogue scales, rating scales, and mood inventories have shown that the effect of loratadine on somnolence, fatigue, and mood was comparable to those found with placebo. In studies exploring physiological indices of CNS functioning, such as EEG-evoked potentials, and sleep latency tests, loratadine has been shown to be free of CNS effects.

Where the evidence is mixed

Pseudoephedrine relieved nasal congestion better than placebo in children aged 6 to 11 with a common cold, but only on day 1. (Source 17)

• Randomized trial, Low certainty.
• Size: children aged 6 to 11 years in a multicenter randomised trial (group sizes not given in the abstract)
• Who: children aged 6 to 11 years with nasal congestion due to the common cold.
• How long: up to 7 days of as-needed dosing; primary endpoint 1 to 8 hours after the first dose.
• Result: Least squares mean difference between treatment groups 1.2 on instantaneous nasal congestion severity (P = .029) on day 1; secondary endpoints on day 2 were only numerically favorable.
• Funding: not stated in the abstract.

Pseudoephedrine was superior to placebo in reducing instantaneous nasal congestion severity in pediatric children over the first 8 hours after dosing on day 1 (least squares mean difference between treatment groups was 1.2; P = .029). Overall, secondary end points associated with nasal congestion were supportive on day 1, whereas secondary end points on day 2 were only numerically favorable.

In a small study of 20 adults the combination did not significantly change objectively measured nasal patency, even though endoscopic measures of swelling and secretion did improve. (Source 21)

• Randomized trial, Very low certainty.
• Size: 20 adults.
• Who: adults with seasonal allergic rhinitis.
• How long: not stated in the abstract.
• Result: Acoustic rhinometry showed a trend toward improvement in nasal patency but the difference between pre- and post-treatment measures was not statistically significant; subjective visual analog scores showed a trend toward improvement in most but not all nasal symptoms.
• Funding: not stated in the abstract.

Limit of this finding: The paper's own description of its design cannot all be true: it calls itself a "double-blind, placebo-controlled, crossover, parallel study", and a study cannot be both crossover and parallel group. It also never says how many of the 20 adults were on placebo. The wording is quoted as published, but the design cannot be relied on, so treat this as a very small exploratory study rather than a controlled comparison.

Acoustic rhinometry detected a trend toward improvement in nasal patency, although the difference between pre- and post-treatment measures was not statistically significant. Endoscopic inferior turbinate photography documented that treatment led to statistically significant reductions in the amount of nasal edema and nasal secretions.

Strong CYP3A4 inhibition raises loratadine blood levels several-fold without lengthening the QTc interval. (Source 9)

• Blood level study, Moderate certainty.
• Size: not stated in the abstract; two randomized three-way crossover studies.
• Who: healthy adult volunteers given loratadine alone, ketoconazole or cimetidine alone, or the combinations for 10 days.
• How long: three 10-day treatments separated by 14-day washouts.
• Result: Loratadine plasma concentrations rose 307% (90% CI 205-428%) with ketoconazole and 103% (70-142%) with cimetidine; QTc change loratadine versus loratadine plus ketoconazole 3.6 ms (90% CI -2.2, 9.4) and versus loratadine plus cimetidine 3.2 ms (-1.6, 7.9), neither statistically significant.
• Funding: not stated in the abstract.

Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events.

Where the research disagrees

Whether oral pseudoephedrine raises blood pressure enough to matter. Pooled randomised data put the average systolic rise at about one millimetre of mercury, and at a similar size (1.20 mm Hg) in people with controlled hypertension, while the label still tells several groups of people to ask a doctor before use. A small average can hide larger rises in individuals, and the meta-analysis itself found higher doses and immediate-release preparations produced greater rises

• Salerno and colleagues, meta-analysis of randomised placebo-controlled trials, meta-analysis of twenty-four randomised placebo-controlled trials with extractable vital sign information (45 treatment arms; 1285 patients): Pseudoephedrine caused a small but significant increase in SBP (0.99, mm Hg; 95% CI, 0.08 to 1.90) and HR (2.83 beats/min; 95% CI, 2.0 to 3.6), with no effect on DBP (0.63 mm Hg, 95% CI, -0.10 to 1.35). (Source 14)
• The US OTC Drug Facts label, regulatory position, over-the-counter Drug Facts label updated December 2025: Ask a doctor before use if you have heart disease thyroid disease high blood pressure diabetes trouble urinating due to an enlarged prostate gland liver or kidney disease. Your doctor should determine if you need a different dose. (Source 7)

Whether antihistamine-decongestant combinations are worth taking for a cold. The same Cochrane review reports a measurable pooled benefit on global effectiveness and then concludes that the effect on individual symptoms is probably too small to matter, that the benefits must be weighed against the risk of adverse effects, and that there is no evidence of effectiveness in young children

• Cochrane review, pooled effectiveness result, systematic review; 14 antihistamine-decongestant trials (1298 participants), of which six studies were pooled for global effectiveness: 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). (Source 15)
• The same review's authors' conclusions, systematic review, the authors' own conclusions: Based on these scarce data, the effect on individual symptoms is probably too small to be clinically relevant. (Source 19)

How much

• Reference intake: There is no reference intake: this is a medicine. As an OTC label position dated 2025, each extended-release tablet contains loratadine 10 mg as the antihistamine and pseudoephedrine sulfate 240 mg as the nasal decongestant. (Source 1)
• Upper limit: As an OTC label position dated 2025, the stated maximum for adults and children 12 years and over is 1 tablet daily and not more than 1 tablet in 24 hours; the tablet is not to be divided, crushed, chewed or dissolved. (Source 22)
• Studied: The 874-patient trial gave a combination of loratadine 10 mg in the coating with pseudoephedrine sulfate 240 mg in an extended-release core once daily, compared against loratadine 10 mg once daily, pseudoephedrine sulfate 120 mg every 12 hours, and placebo, for 2 weeks. (Source 23)
• Studied: The 469-patient trial compared the once-daily tablet (loratadine 10 mg plus pseudoephedrine sulfate 240 mg) against the twice-daily tablet (loratadine 5 mg plus pseudoephedrine sulfate 120 mg) and placebo for 2 weeks. (Source 13)
• Studied: A 28-day multicenter trial gave loratadine 5 mg plus pseudoephedrine 120 mg twice a day or placebo. (Source 11)
• Studied: The pollen-chamber study used single immediate-release doses of pseudoephedrine 60 mg and phenylephrine 12 mg against placebo. (Source 24)

A common belief, and what the research shows

The belief: It says non-drowsy, so it has no side effects worth worrying about.

What the research shows: Non-drowsy describes the loratadine half. The decongestant half does the opposite of sedating. In the 469-patient placebo-controlled trial, "Insomnia was reported significantly more often (P < 0.01) in Claritin-D 12 Hour (15%) patients compared with Claritin-D 24 Hour (4%) and placebo (2%) patients. Dry mouth was reported significantly more often (P < 0.05) in Claritin-D 24 Hour (13%) and Claritin-D 12 Hour (13%) groups compared with placebo (4%)." The label itself warns to stop and ask a doctor if "nervousness, dizziness or sleeplessness occurs" (sources: kaiser-1998-ajt, claritind-label-warnings-2025).

Questions and answers

What is it?

It is one tablet containing two separate medicines. Loratadine is the antihistamine; pseudoephedrine sulfate is the nasal decongestant. In the extended-release US product the amounts are loratadine 10 mg, labelled as the antihistamine, and pseudoephedrine sulfate 240 mg, labelled as the nasal decongestant. Loratadine is a second-generation antihistamine, meaning it blocks the H1 receptor as strongly as the older ones but barely enters the brain. (Source 1)

What does it do in the body?

The loratadine blocks H1 histamine receptors, which is what drives sneezing, runny nose, itchy nose and throat and itchy watery eyes in an allergic reaction. The pseudoephedrine constricts blood vessels in the nose; that vasoconstriction shrinks the swollen lining and opens the airway. The two act on different symptoms, which is why the combination beat each component alone in trials on the symptoms the other component targets. (Source 20)

Is it good or bad for you?

Good for a blocked, streaming nose from hay fever; much weaker and more arguable for a cold; useless and harmful for glue ear in children. The dividing line is the decongestant, which carries the side effects: insomnia was reported in 15% on the 12-hour tablet against 2% on placebo, and dry mouth in 13% against 4%. For people with heart disease, high blood pressure, thyroid disease, diabetes or prostate trouble, the label says ask a doctor first. (Source 13)

How do you get more of it?

Neither ingredient comes from food. Both are synthetic drugs, sold over the counter in the United States, with pseudoephedrine kept behind the pharmacy counter in many places because it can be converted into methamphetamine. The label's dose is fixed and low: one tablet daily for adults and children 12 and over, not more than one in 24 hours, swallowed whole. (Source 22)

If it is harmful, what reduces it?

Stopping the tablet is the whole of it; there is no antidote and nothing to flush out. Pseudoephedrine's effects wear off as the drug clears. In the four reported cases of ischaemic colitis, all responded to abstinence from pseudoephedrine plus medical supportive therapy, and none relapsed in the 8-12 months after discontinuing it. (Source 12)

Why might someone be low in it or missing it?

Nobody is deficient in either ingredient: they are medicines, not nutrients. The nearest real question is why someone with a blocked allergic nose might not be getting relief, and one answer from the trials is that an antihistamine alone does less for stuffiness than the combination: the combination was superior to loratadine alone for nasal stuffiness at end point. (Source 2)

Which whole foods contain it or feed it?

No whole food contains loratadine or pseudoephedrine, and no food supplies either. Both are synthetic drugs. We searched Europe PMC for food and dietary sources and for food interactions and found none for this combination; the one dietary-adjacent interaction we could document was alcohol, which has its own entry. (Source 1)

We searched: Europe PMC REST searches for loratadine or pseudoephedrine combined with food, diet, grapefruit and caffeine; the Drug Facts label for Claritin-D 24 Hour

What happens if you do not have it?

Nothing happens from not taking it; untreated hay fever simply continues. The placebo arms of the trials show the size of what is left untreated: in the common cold review, 55% of people on placebo had a favourable response by the final evaluation day against 70% on active treatment, so most people get better either way and the drug shifts the odds rather than deciding the outcome. (Source 15)

How can you test for it?

There is no clinical test for either drug that a member of the public would be offered. What is worth monitoring if you take it regularly is blood pressure and heart rate, because the pooled randomised evidence shows a small average rise: systolic pressure +0.99 mm Hg (95% CI, 0.08 to 1.90) and heart rate +2.83 beats/min (95% CI, 2.0 to 3.6), with no effect on diastolic pressure. (Source 14)

References

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2. Journal of Allergy and Clinical Immunology. Comparative efficacy and safety of a once-daily loratadine-pseudoephedrine combination versus its components alone and placebo in the management of seasonal allergic rhinitis. — abstract, Results. 1995. PMID 7636050, DOI 10.1016/s0091-6749(95)70001-3. Read the source
3. DailyMed / Bayer HealthCare LLC. CLARITIN-D 24 HOUR (loratadine and pseudoephedrine sulfate) extended release tablet — Drug Facts, Uses. 2025. Read the source
4. Annals of Allergy, Asthma & Immunology. A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber. — abstract, Results. 2009. PMID 19230461, DOI 10.1016/s1081-1206(10)60240-2. Read the source
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6. European Journal of Dermatology. Emedastine difumarate versus loratadine in chronic idiopathic urticaria: a randomized, double-blind, controlled European multicentre clinical trial.. 2006. PMID 17229605. Read the source
7. DailyMed / Bayer HealthCare LLC. CLARITIN-D 24 HOUR (loratadine and pseudoephedrine sulfate) extended release tablet — Drug Facts, Warnings. 2025. Read the source
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12. American Journal of Gastroenterology. Ischemic colitis associated with pseudoephedrine: four cases. — abstract, Results. 1999. PMID 10484004, DOI 10.1111/j.1572-0241.1999.01369.x. Read the source
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15. Cochrane Database of Systematic Reviews. Oral antihistamine-decongestant-analgesic combinations for the common cold. — abstract, Main results. 2022. PMID 35060618, DOI 10.1002/14651858.cd004976.pub4. Read the source
16. American Journal of Gastroenterology. Ischemic colitis associated with pseudoephedrine: four cases. — abstract, Methods. 1999. PMID 10484004, DOI 10.1111/j.1572-0241.1999.01369.x. Read the source
17. Journal of Clinical Pharmacology. A Multicenter, Randomized, Placebo-Controlled Study of Pseudoephedrine for the Temporary Relief of Nasal Congestion in Children With the Common Cold.. 2019. PMID 31274197, DOI 10.1002/jcph.1472. Read the source
18. British Journal of Clinical Pharmacology. Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse.. 2007. PMID 17116124, DOI 10.1111/j.1365-2125.2006.02833.x. Read the source
19. Cochrane Database of Systematic Reviews. Oral antihistamine-decongestant-analgesic combinations for the common cold. — abstract, Authors' conclusions. 2022. PMID 35060618, DOI 10.1002/14651858.cd004976.pub4. Read the source
20. Clinical and Experimental Allergy. Loratadine: a non-sedating antihistamine. Review of its effects on cognition, psychomotor performance, mood and sedation.. 1999. PMID 10444229, DOI 10.1046/j.1365-2222.1999.0290s3147.x. Read the source
21. Ear, Nose & Throat Journal. Loratadine/pseudoephedrine for nasal symptoms in seasonal allergic rhinitis: a double-blind, placebo-controlled study.. 2000. PMID 10786387, DOI 10.1177/014556130007900410. Read the source
22. DailyMed / Bayer HealthCare LLC. CLARITIN-D 24 HOUR (loratadine and pseudoephedrine sulfate) extended release tablet — Drug Facts, Directions. 2025. Read the source
23. Journal of Allergy and Clinical Immunology. Comparative efficacy and safety of a once-daily loratadine-pseudoephedrine combination versus its components alone and placebo in the management of seasonal allergic rhinitis. — abstract, Methods. 1995. PMID 7636050, DOI 10.1016/s0091-6749(95)70001-3. Read the source
24. Annals of Allergy, Asthma & Immunology. A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber. — abstract, Methods. 2009. PMID 19230461, DOI 10.1016/s1081-1206(10)60240-2. Read the source