"By Matt McMillen
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April 9, 2015 -- Spring is finally here, and with it comes tree pollen. For people with allergies, that could spell misery. But despite the hars"...
The following information is based upon studies of loratadine alone or pseudoephedrine alone, except as indicated.
Human histamine skin wheal studies following single and repeated oral doses of loratadine have shown that the drug exhibits an antihistaminic effect beginning within 1 to 3 hours, reaching a maximum at 8 to 12 hours, and lasting in excess of 24 hours. There was no evidence of tolerance to this effect developing after 28 days of dosing with loratadine.
Pharmacokinetic studies following single and multiple oral doses of loratadine in 115 volunteers showed that loratadine is rapidly absorbed and extensively metabolized to an active metabolite (descarboethoxyloratadine). Approximately 80% of the total dose administered can be found equally distributed between urine and feces in the form of metabolic products after 10 days. The mean elimination half-lives found in studies in normal adult subjects (n = 54) were 8.4 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for the major active metabolite (descarboethoxyloratadine). In nearly all patients, exposure (AUC) to the metabolite is greater than exposure to parent loratadine. Loratadine and descarboethoxyloratadine reached steady-state in most patients by approximately the fifth dosing day. The pharmacokinetics of loratadine and descarboethoxyloratadine are dose independent over the dose range of 10 to 40 mg and are not significantly altered by the duration of treatment.
In vitro studies with human liver microsomes indicate that loratadine is metabolized to descarboethoxyloratadine predominantly by P450 CYP3A4 and, to a lesser extent, by P450 CYP2D6. In the presence of a CYP3A4 inhibitor ketoconazole, loratadine is metabolized to descarboethoxyloratadine predominantly by CYP2D6. Concurrent administration of loratadine with either ketoconazole, erythromycin (both CYP3A4 inhibitors), or cimetidine (CYP2D6 and CYP3A4 inhibitor) to healthy volunteers was associated with significantly increased plasma concentrations of loratadine (see DRUG INTERACTIONS).
In a study involving 12 healthy geriatric subjects (66 to 78 years old), the AUC and peak plasma levels (Cmax) of both loratadine and descarboethoxyloratadine were significantly higher (approximately 50% increased) than in studies of younger subjects. The mean elimination half-lives for the elderly subjects were 18.2 hours (range = 6.7 to 37 hours) for loratadine and 17.5 hours (range = 11 to 38 hours) for the active metabolite.
Loratadine; Pseudoephedrine Sulfate 12 hour Extended Release Tablets Only: In the clinical efficacy studies, loratadine was administered before meals. In a single-dose study, food increased the AUC of loratadine by approximately 40% and of descarboethoxyloratadine by approximately 15%. The time of peak plasma concentration (Tmax) of loratadine and descarboethoxyloratadine was delayed by 1 hour with a meal.
In patients with chronic renal impairment (creatinine clearance £30 ml/min) both the AUC and peak plasma levels (Cmax) increased on average by approximately 73% for loratadine; and approximately by 120% for descarboethoxyloratadine, compared to individuals with normal renal function. The mean elimination half-lives of loratadine (7.6 hours) and descarboethoxyloratadine (23.9 hours) were not significantly different from that observed in normal subjects. Hemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite (descarboethoxyloratadine) in subjects with chronic renal impairment.
In patients with chronic alcoholic liver disease the AUC and peak plasma levels (Cmax) of loratadine were double while the pharmacokinetic profile of the active metabolite (descarboethoxyloratadine) was not significantly changed from that in normals. The elimination half-lives for loratadine and descarboethoxyloratadine were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease.
There was considerable variability in the pharmacokinetic data in all studies of loratadine, probably due to the extensive first-pass metabolism. Individual histograms of area under the curve, clearance, and volume of distribution showed a log normal distribution with a 25-fold range in distribution in healthy subjects.
Loratadine is about 97% bound to plasma proteins at the expected plasma concentrations (2.5 to 100 ng/ml) after a therapeutic dose. Loratadine does not affect the plasma protein binding of warfarin and digoxin. The metabolite descarboethoxyloratadine is 73% to 77% bound to plasma proteins (at 0.5 to 100 ng/ml).
Whole body autoradiographic studies in rats and monkeys, radiolabeled tissue distribution studies in mice and rats, and in vivo radioligand studies in mice have shown that neither loratadine nor its metabolites readily cross the blood-brain barrier. Radioligand binding studies with guinea pig pulmonary and brain H1-receptors indicate that there was preferential binding to peripheral versus central nervous system H1-receptors.
In a study in which loratadine alone was administered at four times the clinical dose for 90 days, no clinically significant increase in the QTc was seen on ECGs.
In a single-rising dose study of loratadine alone in which doses up to 160 mg (16 times the clinical dose) were administered, no clinically significnt changes on the QTc interval in the ECGs were observed.
Pseudoephedrine sulfate (d-isoephedrine sulfate) is an orally active sympathomimetic amine which exerts a decongestant action on the nasal mucosa. It is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.
The bioavailability of loratadine; pseudoephedrine sulfate from loratadine; pseudoephedrine sulfate 24 hour extended release tablets is similar to that achieved with separate administration of the components. Coadministration of loratadine and pseudoephedrine does not significantly affect the bioavailability of either component.
In a single-dose study, food increased the AUC of loratadine by approximately 125% and Cmax by approximately 80%. However, food did not significantly affect the pharmacokinetics of pseudoephedrine sulfate or descarboethoxyloratadine.
Loratadine; Pseudoephedrine Sulfate 12 hour Extended Release Tablets Only: The pseudoephedrine component of loratadine; pseudoephedrine sulfate 12 hour extended release tablets was absorbed at a similar rate and was equally available from the combination tablet as from a pseudoephedrine sulfate repetabs 120 mg tablet. Mean (%CV) steady-state peak plasma concentration of 464 ng/mL (22) was attained at 3.9 hours (50). The terminal half-life of pseudoephedrine from the combination tablet administered twice daily was 6.3 hours (23). The ingestion of food was found not to affect the absorption of pseudoephedrine from loratadine; pseudoephedrine sulfate 12 hour extended release tablets. Loratadine and pseudoephedrine sulfate do not influence the pharmacokinetics of each other when administered concomitantly.
12 Hour Extended Release Tablets
Clinical trials of loratadine; pseudoephedrine sulfate 12 hour extended release tablets in seasonal allergic rhinitis involved approximately 3700 patients who received either the combination product, a comparative treatment, or placebo, in double-blind, randomized controlled studies. Four of the largest studies involved approximately 1600 patients in comparisons of the combination product, loratadine (5 mg bid), pseudoephedrine sulfate (120 mg bid), and placebo. Improvement in symptoms of seasonal allergic rhinitis for patients receiving loratadine; pseudoephedrine sulfate 12 hour extended release tablets was significantly greater than the improvement in those patients who received the individual components or placebo. The combination reduced the intensity of sneezing, rhinorrhea, nasal pruritus, and eye tearing more than pseudoephedrine and reduced the intensity of nasal congestion more than loratadine, demonstrating a contribution of each of the components. The onset of antihistamine and nasal decongestant actions occurred after the first dose of loratadine; pseudoephedrine sulfate 12 hour extended release tablets. Loratadine; pseudoephedrine sulfate 12 hour extended release tablets were well tolerated, with a frequency of sedation similar to that seen with placebo, and an adverse event profile clinically similar to that of pseudoephedrine.
24 Hour Extended Release Tablets
Clinical trials of loratadine; pseudoephedrine sulfate 24 hour extended release tablets involved a total of approximately 2000 patients with seasonal allergic rhinitis. One study involved 879 patients, who received either the combination product (loratadine 10 mg and pseudoephedrine sulfate 240 mg), loratadine (10 mg once daily) or pseudoephedrine sulfate (120 mg twice daily) alone, or placebo, in a double-blind randomized design. Improvement in nasal and non-nasal symptoms of seasonal allergic rhinitis including nasal congestion in patients receiving loratadine; pseudoephedrine sulfate 24 hour extended release tablets was significantly greater than in placebo recipients, and generally greater than that achieved with loratadine or pseudoephedrine sulfate alone. In this study, loratadine; pseudoephedrine sulfate 24 hour extended release tablets were well tolerated, with a frequency of sedation similar to that seen with placebo, and a frequency of nervousness and insomnia similar to that seen with pseudoephedrine sulfate given alone.
In another study of 469 patients, once-daily administration of loratadine; pseudoephedrine sulfate 24 hour extended release tablets provided effects similar to those achieved with twice-daily administration of loratadine; pseudoephedrine sulfate 12 hour extended release tablets, a combination product containing 5 mg loratadine plus 120 mg pseudoephedrine sulfate, extended release.
The end of dosing interval efficacy of the pseudoephedrine component of loratadine; pseudoephedrine sulfate 24 hour extended release tablets on the symptom of nasal stuffiness was evaluated in a study of 695 patients who were randomized to receive loratadine; pseudoephedrine sulfate 24 hour extended release tablets, loratadine; pseudoephedrine sulfate tablets, or placebo. Patients who received loratadine; pseudoephedrine sulfate 24 hour extended release tablets had significantly more improvement in nasal stuffiness scores at the end of the dosing interval than those patients receiving loratadine; pseudoephedrine sulfate tablets or placebo throughout the course of the trial.
12 and 24 Hour Extended Release Tablets
In a 6-week, placebo-controlled study of 193 patients with seasonal allergic rhinitis and concomitant mild to moderate asthma, loratadine; pseudoephedrine sulfate 12 and 24 hour extended release tablets twice daily improved seasonal allergic rhinitis signs and symptoms with no decrease in pulmonary function or adverse effect on asthma symptoms. This supports the safety of administering loratadine; pseudoephedrine sulfate 12 and 24 hour extended release tablets to seasonal allergic rhinitis patients with asthma.
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
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