AHFS Class:

• Second Generation Antihistamines 4:08

Generic Name(s):

• Loratadine

Associated Monographs

• Antihistamines General Statement

Loratadine, a derivative of azatadine7,10,31,37,44 , is a second generation antihistamine. 1,2,3,4,5,6,7,8,9,10,36,37,45,46

Loratadine shares the uses of other antihistamines, including the management of allergic rhinitis1,3,4,5,7,8,18,19,44,67,70,71,72,73,74,75 and chronic idiopathic urticaria.1,15,16,17 For additional information on these and other uses of antihistamines, see Uses in the Antihistamines General Statement 4:00.

Allergic Rhinitis

Loratadine alone1,3,4,5,7,8,22,23,44,67,71,72,74 or in fixed combination with pseudoephedrine sulfate 18,19,39,47,70,73,75 is used for self-medication to provide symptomatic relief of seasonal allergic rhinitis (e.g., hay fever).1,3,4,5,7,8,18 19,44,67,70,71,72,73,74,75,76,77 Antihistamines are not curative and merely provide palliative therapy; since seasonal allergic rhinitis may be a chronic, recurrent condition, successful therapy often may require long-term, intermittent use of these drugs.11,12,13,14 In the treatment of seasonal allergic rhinitis, antihistamines are more likely to be beneficial when therapy is initiated at the beginning of the hay fever season when pollen counts are low.12,14,25,27 Antihistamines are less likely to be effective when pollen counts are high, when pollen exposure is prolonged, and when nasal congestion is prominent. 14,26 Chronic nasal congestion and headache caused by edema of the paranasal sinus mucosa often are refractory to antihistamine therapy.12,13,14,28 Antihistamines generally are not effective in relieving symptoms of nasal obstruction.12,13,29

In patients with seasonal allergic rhinitis, loratadine alone1,74 or in fixed combination with pseudoephedrine hydrochloride39,47,75 generally provides symptomatic relief of rhinorrhea,1,18,19,39,44,47,74,75 sneezing,1,18,19,39,44,47,74,75 oronasopharyngeal irritation or itching,1,18,19 39,44,47,74,75 lacrimation,1,18,19,39,47,74,75 and red, irritated, or itching eyes.1,18,19,39,47,74,75 Tablets containing loratadine in fixed combination with pseudoephedrine hydrochloride also provide symptomatic relief of nasal congestion;18,19,39,47,75 loratadine alone may provide some relief, but is generally less effective in relieving nasal congestion than other symptoms of seasonal allergic rhinitis.39,44,47 Tablets containing loratadine in fixed combination with pseudoephedrine hydrochloride generally should only be used when both the antihistaminic and nasal decongestant activity of the combination preparation are needed concurrently.18,19

Relief of symptoms associated with rhinitis usually begins within about 1 hour following initiation of loratadine therapy.7,10,39 Loratadine is more effective than placebo in providing symptomatic relief4,5,7,37,39 and appears to be as effective as other currently available antihistamines, including astemizole (no longer commercially available in the US),4,7,39 azatadine,10,39 chlorpheniramine,7,39 clemastine,4,7,37,39 or terfenadine (no longer commercially available in the US).4,5,7,21,37,39 However, loratadine reportedly is associated with a lower incidence of adverse effects, especially CNS effects, than azatadine,39 cetirizine,39 chlorpheniramine,39 or clemastine,4,7,10,37,39 and the incidence of CNS adverse effects appears to be similar to that associated with astemizole, terfenadine, or placebo.4,5,7,10,21,37,39,40 Although the incidence of adverse CNS effects is low when loratadine is administered at the recommended dosage of 10 mg daily, there is evidence that drowsiness may occur at higher dosages (e.g., 20-40 mg).44 The incidence of adverse anticholinergic effects (e.g., dry mouth) also is low and comparable to that reported for placebo.1,5,10,21,36,37,39,40 In one controlled study comparing 4 weeks of oral loratadine therapy (10 mg daily) to that with intranasal administration of fluticasone (200 mcg daily) in patients 12-17 years of age with moderate to severe seasonal allergic rhinitis, fluticasone was more effective than loratadine in providing relief from rhinitis nasal symptoms (e.g., nasal itching, nasal obstruction, sneezing, rhinorrhea) as reflected in both mean symptom severity scores and the median percentage of symptom-free days;39,48 however, there was no substantial difference between the loratadine and fluticasone treatment groups in the relief of ocular irritation manifestations.39,48

Loratadine also is used for self-medication to provide symptomatic relief of seasonal allergic rhinitis in children 2-12 years of age.1,21,72,74,76,77 Efficacy of loratadine for symptomatic management of seasonal allergic rhinitis in children 2-12 years of age is based on extrapolation of the demonstrated efficacy of loratadine in adults and the likelihood that the disease course, pathophysiology, and drug activity are substantially similar between the 2 populations.1 Safety of loratadine in children 2-5 and 6-12 years of age is based on clinical trials in which the drug was administered orally once daily at dosages of 5 and 10 mg, respectively, for 2 weeks.1 Recommended pediatric doses were based on cross-study comparisons of the pharmacokinetics of loratadine in adults and children and on safety profiles of the drug from studies in adults and children at recommended or higher doses.1

Loratadine also has been used for the symptomatic treatment of perennial allergic rhinitis†.39 In several short-term (3-4 week) studies, loratadine (10 mg once daily) was as effective as clemastine (1 mg twice daily), or terfenadine (60 mg twice daily) and more effective than placebo in providing symptomatic relief of perennial allergic rhinitis.39 In a long-term (6 month) study comparing the efficacy of loratadine (10 mg daily) and clemastine (1 mg twice daily) in patients with perennial allergic rhinitis, loratadine was as effective as clemastine in providing symptomatic relief of perennial allergic rhinitis, and was more effective in relieving nasal obstruction than clemastine after 1 week of treatment.39 Limited data indicate that loratadine (2.5-5 mg daily) was as effective as dexchlorpheniramine (0.5-1 mg every 8 hours) in relieving the symptoms of perennial allergic rhinitis in children.39 Further study is needed to determine the exact role of loratadine in the treatment of perennial allergic rhinitis.9 Although the efficacy of loratadine has not been determined, antihistamines generally are less effective in the treatment of perennial nonallergic (vasomotor) rhinitis† than in allergic rhinitis.13,24,25,26

Chronic Idiopathic Urticaria

Loratadine is used for self-medication to provide symptomatic relief of pruritus, erythema, and urticaria associated with chronic idiopathic urticaria (e.g., hives).1,15,16,17,78 Safety and efficacy of loratadine were established in controlled studies of patients 12 years of age and older with chronic idiopathic urticaria receiving the drug at a dosage of 10 mg daily or placebo.1 In these studies, loratadine was superior to placebo in relieving associated pruritus, erythema, and urticaria.1 The manufacturer states that loratadine does not prevent chronic idiopathic urticaria or allergic skin reactions.78

Loratadine also is used for self-medication to provide symptomatic relief of pruritus, erythema, and urticaria associated with chronic idiopathic urticaria in children 6-12 years of age.78 Loratadine is not recommended for self-medication in children younger than 6 years of age.78 The drug formerly was commercially available in the US only as a prescription drug.1 At that time, loratadine was approved for the management of chronic idiopathic urticaria in children 2 years of age and older, and the drug can continue to be used in this age group under the direction of a clinician.1 Efficacy of loratadine for symptomatic relief of chronic idiopathic urticaria in children 2-12 years of age is based on extrapolation of the demonstrated efficacy of loratadine in adults and the likelihood that the disease course, pathophysiology, and drug activity are substantially similar between the 2 populations.1 Recommended pediatric doses are based on cross-study comparisons1 of the pharmacokinetics of loratadine in adults and children1 and on safety profiles of the drug from studies in adults and children at recommended or higher doses.1

Administration

Loratadine is administered orally.1,2,3,4,5,6,7,8,18,19,67,70,71,72,73,74,76,77 Loratadine conventional tablets, orally disintegrating tablets, and the commercially available tablets containing the drug in fixed combination with pseudoephedrine sulfate can be administered without regard to meals.1,18,20

Although the oral bioavailability of loratadine is increased when the drug is administered as the orally disintegrating tablet without water, the bioavailability of the active metabolite desloratadine (descarboethoxyloratadine) is unaffected,1 and the manufacturers state that the orally disintegrating tablets can be administered with or without water.1,67,68,74 The orally disintegrating tablets are administered by placing a tablet on the tongue, where it disintegrates within a few seconds, and then subsequently swallowing with or without water.1,68,71 Tablets containing loratadine in fixed combination with pseudoephedrine sulfate should be swallowed intact and patients should be instructed not to break, chew, or dissolve such tablets.18,19,70,73,75,76 Patients also should be instructed to take Claritin-D^® 24 Hour extended-release tablets with a full glass of water.19,70

Dosage

Allergic Rhinitis and Chronic Idiopathic Urticaria

For symptomatic relief of seasonal allergic rhinitis, the usual dosage of loratadine for self-medication 65,66,74 in adults and children 6 years of age and older is 10 mg once daily.1,5,7,10,67,68,69,74,77 The usual dosage for self-medication 65,66 in children 2 to under 6 years of age is 5 mg once daily as the syrup.1,72 When loratadine is used in fixed combination with pseudoephedrine sulfate in a twice-daily (12-hour) formulation for symptomatic relief of allergic rhinitis in adults and children 12 years of age and older, the usual dosage for self-medication 65,66,75 is 5 mg of loratadine twice daily (every 12 hours).18,73,75,76 Alternatively, when the fixed combination containing loratadine with pseudoephedrine sulfate (Claritin-D^® 24-Hour) in a once-daily (24-hour) formulation is used for symptomatic relief of allergic rhinitis in adults and children 12 years of age and older, the usual dosage for self-medication 65,66 is 10 mg of loratadine once daily.19,70

For the management of chronic idiopathic urticaria, the usual dosage of loratadine for self-medication in adults and children 6 years of age and older is 10 mg once daily.1,78 Although loratadine currently is not labeled for self-medication in children younger than 6 years of age,78 the drug can be used under the direction of a clinician at a prescribed dosage of 5 mg once daily for the management of chronic idiopathic urticaria in children 2-5 years of age.1

While the risk of adverse CNS effects (e.g., drowsiness) appears to be low with the usual dosage of loratadine, the risk is dose related, increasing with dosages 2-4 times the usual dosage.1 The risk of such effects may be particularly likely in geriatric patients and in those with hepatic or renal impairment, even at usual dosages.1,15 The adverse effect profile in pediatric patients 6-12 years of age receiving 10 mg of the drug daily was similar to that of adults.1

Dosage in Renal and Hepatic Impairment

In patients with chronic renal impairment (creatinine clearance of 30 mL/minute or less), both oral bioavailability and peak plasma concentrations of loratadine and desloratadine may be increased compared with individuals with normal renal function.1,18,19 However, elimination half-lives of the drug and its active metabolite appear to be similar to those of individuals with normal renal function.1,18,19 Patients with renal impairment receiving loratadine for self-medication should be advised to consult a clinician before initiating therapy, since a different dosage may be recommended.67,68,69,70,71,72,73,74,78 Therapy with loratadine conventional or orally disintegrating tablets or oral solution should be initiated at a dosage of 10 mg every other day in adults and children 6 years of age and older with a glomerular filtration rate less than 30 mL/minute1,18 and at a dosage of 5 mg every other day in children 2-5 years of age with renal insufficiency.1 In addition, therapy with the commercially available tablets containing loratadine in fixed combination with pseudoephedrine sulfate should be initiated in adults and children 12 years of age and older with a glomerular filtration rate less than 30 mL/minute at a dosage of 5 mg once daily when the 12-hour formulation is used or at a dosage of 10 mg every other day when the 24-hour formulation is used, since clearance of both loratadine and pseudoephedrine are decreased in such patients.18,19 Hemodialysis does not appear to affect the pharmacokinetics of loratadine or desloratadine.1,4,10,18,19

The pharmacokinetics of loratadine and its active metabolite also may be altered in patients with hepatic impairment and dosage adjustment may be necessary.1 Therefore, patients with hepatic impairment receiving loratadine for self-medication should be advised to consult a clinician before initiating therapy, since a different dosage may be recommended.67,68,69,70,71,72,73,78 Therapy with loratadine conventional or orally disintegrating tablets or oral solution should be initiated at a dosage of 10 mg every other day in adults and children 6 years of age and older with hepatic failure1 and at a dosage of 5 mg every other day in children 2-5 years of age with hepatic failure.1 Since fixed-ratio combination preparations do not permit individual titration of dosages, and clearance of loratadine is decreased more substantially than that of pseudoephedrine sulfate in patients with hepatic impairment, the manufacturer recommends that tablets containing loratadine in fixed combination with pseudoephedrine sulfate generally not be used in such patients.18,19

Adverse reactions to loratadine occur relatively infrequently, are dose related, and usually are transient and mild in severity.1,2,4,5,7,10,16,17,18,19,20,23,36,37,39,44,46,47,58,61,63 During controlled clinical trials in adolescent and adult patients 12 years of age and older receiving conventional tablets, solution, or orally disintegrating tablets orally, the incidence of loratadine-induced adverse effects was similar to that reported with placebo.1,2,4,5,7,10,16,17,23,36,37,39,44,47,59,60,61 The incidence of adverse reactions (except for the increased incidence of insomnia and dry mouth) reported with 12-hour extended-release tablets containing loratadine 5 mg in fixed combination with pseudoephedrine sulfate 120 mg also was similar to that reported with placebo,18 and the incidence of adverse reactions reported with 24-hour extended-release tablets containing loratadine 10 mg in fixed combination with pseudoephedrine sulfate 240 mg was similar to that reported in patients receiving twice-daily 120-mg extended-release pseudoephedrine alone.19 About 2% of patients 12 years of age or older receiving either loratadine or placebo and less than 1% of patients 6-12 years of age receiving loratadine discontinued therapy before completion of their respective studies.1 Adverse effects in pediatric patients 6-12 years of age were similar in type and frequency to those observed in adult patients receiving loratadine.1 Adverse effects in children 2-5 years of age receiving loratadine 5 mg orally once daily for 2 weeks in a double-blind, placebo-controlled clinical trial were consistent with the known safety profile of the drug and likely adverse effects in the population studied.1

Although loratadine metabolism, like that of terfenadine (no longer commercially available in the US), is inhibited by certain drugs (e.g., azole antifungal agents) that affect hepatic microsomal enzymes,1,18,19,38,54 unchanged loratadine does not appear to share the cardiotoxic potential of unchanged terfenadine.1,18,19,38,39,53,54 (See Cautions: Cardiovascular Effects.)

CNS Effects

The most frequent adverse effects reported with loratadine are nervous system effects.1 Headache occurred in about 12% of patients receiving loratadine in clinical trials.1 In clinical trials in patients receiving the 12-hour extended-release dosage form of loratadine in fixed combination with pseudoephedrine sulfate, headache occurred in 19% of patients receiving loratadine 5 mg and pseudoephedrine sulfate 120 mg, 18% of those receiving loratadine alone, and 17% of those receiving pseudoephedrine sulfate alone.18 Although headache occurred in more than 2% of patients receiving 24-hour extended-release tablets containing loratadine 10 mg in fixed combination with pseudoephedrine sulfate 240 mg in clinical trials, this effect was reported more frequently in those receiving placebo.19 Sedation (e.g., drowsiness, fatigue) occurred in about 12% (e.g., 8 and 4%, respectively) of patients receiving loratadine in clinical trials.1 The incidence of drowsiness appears to be dose related;23,44 although the incidence of drowsiness in patients receiving 10 mg of loratadine is no greater than that in patients receiving placebo, dose-related drowsiness becomes more prominent with doses of 20-40 mg.23,44 In studies of patients receiving extended-release dosage forms of loratadine in fixed combination with pseudoephedrine sulfate, drowsiness occurred in 6-7% of patients receiving the combination, 4-8% of those receiving loratadine alone, and 5% of those receiving pseudoephedrine sulfate alone.18,19

Insomnia occurs in 5-16% of patients receiving extended-release dosage forms of loratadine in fixed combination with pseudoephedrine sulfate, in 1-4% of those receiving loratadine alone, and 9-19% of those receiving pseudoephedrine sulfate alone.18,19 Nervousness occurred in 3-5% of patients receiving extended-release dosage forms of the drug in fixed combination, in 1-3% of those receiving loratadine alone, and 4-7% of those receiving pseudoephedrine sulfate alone.18,19 In children 6-12 years of age receiving loratadine 10 mg daily or placebo, nervousness occurred in 4 or 2%, fatigue in 3 or 2%, hyperkinesia in 3 or 1%, dysphonia in 2 or less than 1% of patients, respectively.1 Malaise occurred in 2% of patients 6-12 years of age receiving loratadine, but did not occur in those receiving placebo, and occurred in at least one adult or pediatric patient in other clinical studies.1 Fatigue occurred in 2-3% of children 2-5 years of age receiving loratadine in controlled clinical trials and more frequently in patients receiving loratadine than in those receiving placebo.1

Adverse nervous system effects occurring in at least one pediatric or adult patient receiving loratadine in clinical trials include hypoesthesia,1 asthenia,1 dizziness,1 dysphonia,1 hypertonia,1 migraine,1 paresthesia,1 tremor,1 vertigo,1 agitation,1 amnesia,1 anxiety,1 confusion,1 decreased libido,1 depression,1 impaired concentration,1 irritability,1 and morbid dreaming.1 Seizures were reported rarely during postmarketing surveillance of the drug.1

Pulmonary Effects

In patients 6-12 years of age receiving loratadine in clinical trials, wheezing occurred in 4 or 2% of patients receiving loratadine or placebo, respectively,1 and upper respiratory tract infection occurred in 2 or less than 1%, respectively, in this age group.1 Bronchitis, bronchospasm, coughing, dyspnea, hemoptysis, and hiccup occurred in at least one pediatric or adult patient in clinical trials of loratadine.1

Oronasopharyngeal Effects

The most frequent adverse oronasopharyngeal effect reported with loratadine was dry mouth, which occurred in about 3% of patients;1 dry mouth occurred in 8-14% of patients receiving 12- or 24-hour extended-release tablets containing loratadine and pseudoephedrine, but in only 2-4, 7-9, or 2-3%, respectively, of patients receiving loratadine, pseudoephedrine, or placebo in control groups.18,19 Epistaxis and pharyngitis occurred in 2-3% of children 2-5 years of age receiving loratadine in controlled clinical trials and more frequently in patients receiving loratadine than in those receiving placebo.1 Adverse oronasopharyngeal effects occurring in at least one patient in clinical trials of pediatric and adult patients receiving loratadine included altered salivation,1 altered taste,1 laryngitis,1 nasal dryness,1 sinusitis,1 and sneezing.1 Repeated application of loratadine orally disintegrating tablets to the buccal mucosa of animals did not result in local irritation,1 and there was no increased frequency of mouth or tongue irritation when loratadine was administered as orally disintegrating tablets in clinical trials.1

GI Effects

Abdominal pain occurred in about 2% of patients 6-12 years of age receiving loratadine, but not in those receiving placebo.1 Diarrhea, stomatitis, and tooth disorder occurred in 2-3% of children 2-5 years of age receiving loratadine in controlled clinical trials and more frequently in patients receiving loratadine than in those receiving placebo.1 Adverse GI effects occurring in at least one patient in clinical trials of pediatric and adult patients receiving loratadine included anorexia,1 constipation,1 dyspepsia,1 flatulence,1 gastritis,1 increased appetite,1 loose stools,1 nausea,1 and vomiting.1

Mechanical upper GI obstruction after ingestion of a Claritin-D^® 24 Hour tablet, including obstruction requiring endoscopic removal of the tablet, was reported rarely during postmarketing surveillance.30 Many of the individuals in whom upper GI obstruction occurred after ingesting the Claritin-D^® 24 Hour preparation had a history of difficulty in swallowing tablets, a known upper GI narrowing, or abnormal esophageal peristalsis.30 It is not known whether use of the currently available reformulated Claritin-D^® 24 hour tablet is associated with an increased risk of GI obstruction.19

Ocular and Otic Effects

Conjunctivitis occurred in 2% of patients 6-12 years of age receiving loratadine in controlled trials, and in less than 1% of patients receiving placebo.1 Earache occurred in 2-3% of children 2-5 years of age receiving loratadine in controlled clinical trials and more frequently in patients receiving loratadine than in those receiving placebo.1 Blepharospasm, altered lacrimation, blurred vision, ocular pain, earache, and tinnitus occurred in at least one pediatric or adult patient receiving loratadine.1

Sensitivity Reactions

Rash occurred in 2-3% of children 2-5 years of age receiving loratadine in controlled clinical trials and more frequently in those receiving loratadine than in patients receiving placebo.1 In clinical trials of pediatric and adult patients receiving loratadine, angioedema,1 photosensitivity reaction,1 pruritus,1 purpura,1 and urticaria1 occurred in at least one patient. Anaphylaxis1 and erythema multiforme1 occurred rarely in postmarketing surveillance of loratadine.1

Cardiovascular Effects

In clinical trials of adults and children 6 years of age and older receiving loratadine, hypertension,1 hypotension,1 palpitations,1 supraventricular tachyarrhythmias,1 syncope,1 and tachycardia1 occurred in at least one patient.1 Peripheral edema occurred rarely in postmarketing surveillance of loratadine.1

Syncope associated with prolonged QT interval corrected for rate (QT_c) and ventricular arrhythmias were reported within 24 hours after adding loratadine to an existing drug regimen in a geriatric patient.39,52,53,54 However, the patient had a history of similar arrhythmias and was receiving quinidine,39,52,53,54 and return to normal sinus rhythm occurred within hours after discontinuance of both quinidine and loratadine.52,53 The time course of resolution is consistent with rapidly declining plasma quinidine concentrations and inconsistent with the long half-life of loratadine and its active metabolite desloratadine (descarboethoxyloratadine).53 In addition, loratadine did not appear to increase the patient's plasma quinidine concentration, since a specimen obtained at the time of the event produced results similar to those obtained 5 weeks prior to the event, and dosage of quinidine was unchanged.53 Although blockade of the delayed rectifier potassium channel I_k has been demonstrated for quinidine,53 astemizole (no longer commercially available in the US),53 and terfenadine (no longer commercially available in the US),53 and is considered by some clinicians to be the mechanism responsible for torsades de pointes,53 loratadine does not block this potassium channel at plasma concentrations up to 875 times greater than those obtained with recommended dosage of the drug.53,55 Therefore, loratadine does not appear to have cardiotoxic effects,53,54 even at dosages substantially greater than the recommended dosage,53 and does not appear to be responsible for the reported adverse cardiac effect in this patient.39,53,54

Although serious cardiac effects, including ventricular fibrillation and death associated with prolonged QT interval and atypical ventricular arrhythmia (torsades de pointes) have been reported in patients receiving other “second generation” antihistamines (e.g., astemizole, terfenadine), loratadine administered alone to adults at 4 times the recommended daily dosage for 90 days has not been associated with prolongation of the QT_c interval.1,18,19 In a clinical study, administration of loratadine in single doses up to 160 mg (16 times the maximum daily dosage) was not associated with prolongation of the QT_c interval.1,18,19 Concomitant administration of the drug with other drugs known to inhibit cytochrome P-450 (CYP) microsomal enzymes (e.g., ketoconazole, erythromycin, clarithromycin, cimetidine) is associated with substantially increased loratadine and/or desloratadine plasma concentrations in healthy individuals,1,18,19,64 but there are no clinically relevant changes in ECG parameters (e.g., QT_c intervals) associated with such administration.1,18,19,54,64 For more see Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes and also see Cautions: Cardiovascular Effects in the Antihistamines General Statement.

Hepatic Effects

Abnormal hepatic function, including jaundice,1 hepatitis,1 and hepatic necrosis1 were reported rarely during postmarketing surveillance of loratadine.1

Other Adverse Effects

Influenza-like symptoms and viral infections occurred in 2-3% of children 2-5 years of age receiving loratadine in controlled clinical trials and more frequently in patients receiving loratadine than in those receiving placebo.1 Flushing,1 increased sweating,1 dermatitis,1 dry hair,1 dry skin,1 thirst,1 fever,1 weight gain,1 back pain,1 chest pain,1 leg cramps,1 rigors,1 arthralgia,1 myalgia, 1 breast pain,1 dysmenorrhea,1 menorrhagia,1 vaginitis,1 impotence,1 altered micturition,1 urinary discoloration,1 urinary incontinence,1 and urinary retention1 occurred in at least one patient in clinical trials of loratadine.1 Alopecia, thrombocytopenia, and breast enlargement occurred rarely in postmarketing surveillance of loratadine.1

Precautions and Contraindications

The incidence of adverse effects associated with loratadine use generally appears to be less than that associated with the use of first generation (prototypical, sedating) antihistamines, but similar effects have been reported,7,10,16,36,44 and the potential for typical adverse effects induced by these agents should be considered during loratadine therapy. Pharmacologic studies indicate that loratadine does not have appreciable anticholinergic effects at doses exceeding those required for antihistaminic activity,7,10,49 and anticholinergic-like effects (e.g., dryness of the nose) either did not occur, or occurred with a frequency similar to placebo, in clinical studies.1,7,10,18,19,62 If a fixed-combination preparation containing loratadine and pseudoephedrine hydrochloride is used, the precautions and contraindications associated with pseudoephedrine must be considered.18,19

Patients with hepatic impairment or renal insufficiency (e.g., glomerular filtration rate less than 30 mL/minute), including geriatric patients, have decreased clearance of the drug, and should be given a lower initial dose of loratadine.1 Because patients with hepatic impairment experience greater decreases in clearance of loratadine than pseudoephedrine, and the doses of loratadine and pseudoephedrine in the fixed-combination preparations cannot be individually adjusted, these preparations generally should not be used in patients with hepatic insufficiency.18,19 Patients with renal insufficiency should receive a lower initial dosage of the fixed-combination preparations.18,19 (See Dosage and Administration: Dosage.)

Patients receiving loratadine in fixed combination with pseudoephedrine sulfate for self-medication should be advised to consult a clinician before initiating therapy if they have heart disease, hypertension, thyroid disease, diabetes mellitus, or difficulty in urination resulting from enlargement of the prostate.70,73,75

Patients receiving loratadine should be instructed to take the drug only as needed and not to exceed the recommended dosage, because taking more than the recommended dosage may cause drowsiness.18,19,67,70,71,72,73,75,76,77,78 Patients also should be questioned about other drugs (both prescription and those for self-medication) that they are receiving and should be advised against concurrent use of the fixed-combination preparations of loratadine with over-the-counter (OTC) antihistamines and decongestants.18,19 Patients should be instructed to store the drug in a tightly closed container in a cool, dry place, away from heat or direct sunlight, and away from children.1,18,19,67,70,71,72,73,75

Patients receiving loratadine in fixed combination with pseudoephedrine sulfate for self-medication should be instructed to discontinue therapy and contact their clinician if symptoms do not improve within 7 days or are accompanied by fever or if nervousness, dizziness, or sleeplessness occurs.70,73,75

Patients receiving loratadine as self-medication for management of chronic idiopathic urticaria (e.g., hives) should be informed that the drug does not prevent hives resulting from any known cause (e.g., food, drug, insect sting, latex or rubber gloves), and that avoidance of the cause is the only way to prevent occurrence of this dermatologic reaction.78 Prior to initiating loratadine therapy, patients should consult a clinician if they have hives that are unusual in color, that look bruised or blistered, or that do not itch.78 Patients should be warned that hives may present with other severe allergic reactions, including anaphylactic shock (e.g., trouble swallowing, swelling of the tongue, trouble speaking, wheezing or trouble breathing, dizziness or loss of consciousness, swelling in or around the mouth, drooling).78 These manifestations may occur when hives first appear or up to several hours later and can be life-threatening if not treated immediately.78 If anaphylactic shock occurs in conjunction with hives, patients should be advised to seek emergency help immediately .78 Patients should be instructed to discontinue loratadine therapy and contact their clinician if manifestations of chronic idiopathic urticaria do not improve within 3 days or if the hives have persisted for more than 6 weeks.78 In addition, patients who have been prescribed an epinephrine auto-injector for management of anaphylaxis or severe allergic reactions associated with chronic idiopathic urticaria should be advised to carry the epinephrine auto-injector at all times; loratadine should not be used as a substitute for this device.78

Patients should be advised to discontinue loratadine therapy immediately and to contact their clinician if any signs of an allergic reaction occur.67,68,69,70,71,72,73 (See Cautions: Sensitivity Reactions.)

Individuals who must restrict their intake of phenylalanine should be warned that Alavert^® rapidly disintegrating tablets contain aspartame, which is metabolized in the GI tract following oral administration, to provide 8.4 mg of phenylalanine per tablet.68

Loratadine is contraindicated in patients who are hypersensitive to the drug or any ingredient in its formulation.1,18,19 Because of rare postmarketing reports of mechanical upper GI obstruction (including that requiring endoscopic removal) caused by ingestion of Claritin-D^® 24 Hour tablets,19,30 individuals with a history of difficulty in swallowing tablets, a known upper GI narrowing, or abnormal esophageal peristalsis should not use the Claritin-D^® 24 Hour tablet preparation.19,30

Pediatric Precautions

Safety of loratadine in children 2-5 and 6-12 years of age is based on clinical trials in which the drug was administered orally at dosages of 5 and 10 mg daily, respectively, for 2 weeks.1 (See Uses.)

Safety and efficacy of loratadine in children younger than 2 years of age have not been established.1

Safety and efficacy of loratadine in fixed combination with pseudoephedrine sulfate in children younger than 12 years of age also have not been established.18,19

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.83,84 There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by the US Food and Drug Administration [FDA]) for symptomatic treatment of cold and cough have not been established.83 Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of a the agency continues to assess safety and efficacy of these preparations in older children. FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in the Antihistamines General Statement 4:00.

Geriatric Precautions

Although limited data from a study of patients 66-78 years of age indicate that the peak plasma concentration and AUC of loratadine and desloratadine are increased in geriatric patients,1 safety and efficacy of the drug in geriatric patients have not been studied specifically to date.1 Because geriatric patients frequently have decreased renal function (e.g., glomerular filtration), particular attention should be paid to evaluating renal function prior to initiation of loratadine and subsequently thereafter in this age group. If evidence of renal impairment exists or develops, appropriate adjustments in dosage should be made.1 (See Dosage and Administration: Dosage in Renal Impairment.)

Safety and efficacy of loratadine in fixed combination with pseudoephedrine in geriatric patients 60 years of age and older have not been studied to date.18,19 However, geriatric patients may be especially sensitive to, and are more likely to have adverse effects from, administration of sympathomimetic amines than younger patients.18,19 Extended-release preparations containing pseudoephedrine therefore should not be administered to these patients until safety has been established by administration of a short-acting preparation. For further information about the effects of pseudoephedrine in geriatric patients, see Precautions and Contraindications in Pseudoephedrine 12:12.12.

Mutagenicity and Carcinogenicity

No evidence of loratadine-induced mutagenesis was seen in the reverse (Ames) or forward point mutation (CHO-HGPRT) assays, the rat primary hepatocyte unscheduled DNA assay for DNA damage, or in 2 assays for chromosomal damage (human peripheral blood lymphocyte clastogenesis assay, mouse bone marrow erythrocyte micronucleus assay).1 A positive finding occurred in the nonactivated but not in the activated phase of the mouse lymphoma assay.1

In animal carcinogenicity studies, mice received daily oral loratadine dosages of up to 40 mg/kg for 18 months, and rats received up to 25 mg/kg daily for 2 years, and plasma AUCs of loratadine and its active metabolite desloratadine were obtained to determine the exposure of the animals to the drug.1 The achieved plasma AUCs of loratadine and desloratadine were 3.6 and 18 times higher in mice given 40 mg/kg, 28 and 67 times higher in rats given 25 mg/kg, and 10 and 15 times higher in rats given 10 mg/kg, respectively, than in adults given the maximum recommended oral daily dosage.1,18,19 Also, the achieved plasma AUCs of loratadine and desloratadine were 5 and 20 times higher in mice given 40 mg/kg, 40 and 80 times higher in rats given 25 mg/kg, and 15 and 20 times higher in rats given 10 mg/kg, respectively, than in children given the maximum recommended oral daily dosage.1 Although hepatocellular tumors (combined adenomas and carcinomas) occurred more frequently in male mice administered 40 mg/kg, in male rats administered 10 mg/kg, or male and female rats administered 25 mg/kg of loratadine daily than in control animals in these studies, the clinical importance of these findings in long-term use of the drug in humans is unknown.1,18,19

Pregnancy, Fertility, and Lactation

Pregnancy

An increased incidence of hypospadias in male infants born to women who received loratadine during pregnancy was reported in one study.81,82 However, analysis of data from the National Birth Defects Prevention Study (NBDPS) indicated that use of loratadine during early pregnancy was not associated with an increased risk of second- or third-degree hypospadias.81 In addition, in 2 small prospective cohort studies that surveyed pregnant women who contacted a teratology information service, use of loratadine during the first trimester of pregnancy was not associated with major congenital anomalies and did not affect the rate of live birth, gestational age at birth, and birth weight.79,80 Despite these findings, it should be noted that interpretation of these results is limited by the statistical limitations of the studies (i.e., small sample size, inadequate power, reliance on patient recall of drug use, exclusion criteria).79,80,81 The 2 prospective cohort studies were powered to detect statistical significance only if a substantial (i.e., approximately threefold) increase in the overall rate of major congenital anomalies was observed;79,80 the study that relied on NBDPS data excluded first-degree hypospadias because of the difficulty of detecting this mildest form in routine surveillance, making it difficult to determine the relationship between loratadine and this form of hypospadias.81 Thus, while these data may be useful, further study is needed to completely rule out the teratogenic risk of loratadine.79 Because there are no adequate and controlled studies to date using loratadine in pregnant women, loratadine alone or in fixed combination with pseudoephedrine hydrochloride should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,19 Reproduction studies in rats and rabbits using loratadine dosages up to 75 and 150 times, respectively, the maximum daily human dosage on a mg/m² basis have not revealed evidence of harm to the fetus.1

Fertility

Decreased fertility (i.e., lower female conception rates), which was reversible by discontinuing the drug, occurred in male rats at an oral loratadine dosage of 64 mg/kg (about 50 times the maximum recommended human daily oral dosage on a mg/m² basis).1 Studies in female and male rats using loratadine dosages of about 24 mg/kg (20 times the maximum recommended human daily oral dosage on a mg/m² basis) have not revealed evidence of impaired fertility or reproduction.1

Lactation

Loratadine and desloratadine distribute readily into breast milk, achieving concentrations that are equivalent to those in plasma (i.e., a milk to plasma AUC ratio of 1.17 and 0.85, respectively).1 The manufacturer states that about 0.03% of a single 40-mg dose of loratadine was distributed into breast milk as loratadine and desloratadine over 48 hours.1 Pseudoephedrine also distributes readily into breast milk.18,19 Caution should be exercised when loratadine is administered alone or in fixed combination with pseudoephedrine to a nursing woman, and a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,18,19

Drugs Affecting Hepatic Microsomal Enzymes

Although increased plasma concentrations (AUC _0-24h) of loratadine and its active metabolite desloratadine (descarboethoxyloratadine) have been reported when the drug was concomitantly administered with therapeutic dosages of ketoconazole, erythromycin, clarithromycin, or cimetidine in controlled clinical pharmacology studies in healthy individuals, no clinically important changes in ECG or laboratory evaluations, vital signs, or adverse effects were reported.1,18,19,39,64 Unlike unchanged terfenadine (no longer commercially available in the US), unchanged loratadine does not appear to be cardiotoxic.39,53,54,64 (See Cautions: Cardiovascular Effects.) For further information about these and other drug interactions with loratadine, see Drug Interactions in the Antihistamines General Statement 4:00.

Monoamine Oxidase Inhibitors

No specific drug interaction studies have been conducted with fixed-combination extended-release tablets containing loratadine and pseudoephedrine sulfate.18,19 Because monoamine oxidase (MAO) inhibitors potentiate the pressor effects of sympathomimetic drugs (e.g., pseudoephedrine), fixed-combination extended-release tablets containing loratadine and pseudoephedrine are contraindicated in patients receiving an MAO inhibitor, or for 2 weeks after discontinuance of an MAO inhibitor.18,19 For further information about drug interactions with pseudoephedrine, see Pseudoephedrine Hydrochloride 12:12.12.

Other Drugs

Loratadine does not affect plasma protein binding of warfarin or digoxin.18,19 No apparent increase in adverse effects occurred in individuals receiving oral contraceptives concomitantly with loratadine.1

Laboratory Test Interferences

In vitro addition of pseudoephedrine to sera containing the cardiac isoenzyme MB of serum creatinine phosphokinase progressively inhibits the activity of the enzyme, resulting in complete inhibition over 6 hours.18,19

Acute Toxicity

Pathogenesis

The acute lethal dose of loratadine in humans is not known. The oral LD₅₀ of loratadine exceeds 5 g/kg in mature rats and in mice.1,18,19 No deaths occurred when loratadine was administered to mature rats or mice at doses up to 5 g/kg (approximately 2400 and 2900 times or approximately 1200 and 1400 times, respectively, the maximum recommended adult and pediatric oral daily dosages on a mg/m² basis). 1,19 Similarly, when the drug was administered to monkeys at doses up to 1280 mg/kg (approximately 2100 and 1500 times, respectively, the maximum recommended adult and pediatric oral daily dosages on a mg/m² basis), no deaths occurred.1 However, lethality occurred when loratadine was administered to juvenile rats at a dose of 125 mg/kg (approximately 100 and 70 times, respectively, the maximum recommended adult and pediatric oral daily dosages on a mg/m² basis).1

Manifestations

In adults, drowsiness, tachycardia, and headache have been reported after overdoses (e.g., 40-180 mg) of loratadine tablets.1,18,19 In children, extrapyramidal manifestations and palpitations have been reported with overdoses (exceeding 10 mg) of loratadine syrup.1

Treatment

Treatment of loratadine overdosage generally involves symptomatic and supportive care, initiated promptly and maintained as long as necessary.1,18,19 In acute loratadine overdosage, the stomach should be emptied immediately by inducing emesis with ipecac syrup.1,18,19 Administration of activated charcoal after emesis may be useful in preventing absorption of loratadine.1,18,19 If induction of vomiting is unsuccessful or contraindicated (e.g., the patient is comatose, having seizures, or lacks the gag reflex), gastric lavage with a 0.9% sodium chloride solution may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.1,18,19,24 Saline cathartics may be of value to rapidly dilute bowel contents.1,18,19 Loratadine is not removed by hemodialysis.1,18,19 It is not known if loratadine is removed by peritoneal dialysis.1,18,19

Pharmacology

Loratadine is a long-acting antihistamine.1,2,3,4,5,6,7,8,9,10,18,19,36,46 The drug has been characterized as a specific, selective peripheral H₁-receptor antagonist and has been referred to as a relatively “nonsedating” or second generation antihistamine.1,2,3,4,5,6,7,8,9,10,36,37,45,46 The pharmacology of loratadine resembles that of other currently available antihistamines;7,44 however, the overall pharmacologic profile of loratadine differs from that of these other drugs.1,7,10,18,19,44,49 Experimental evidence indicates that the drug exhibits competitive, specific, and selective antagonism of histamine H₁-receptors.7 Although the exact nature of loratadine's interaction at the H₁-receptor is unknown, disposition of the drug suggests that the prolonged nature of loratadine's antagonism of histamine may result from the drug's slow dissociation from the H₁-receptors or the formation of the active metabolite, desloratadine (descarboethoxyloratadine).7

In vitro, loratadine exhibits a threefold greater affinity for peripheral histamine H₁-receptors than it does for those from brain tissues,1,7,10,18,19,37,44 whereas terfenadine (no longer commercially available in the US) exhibits a similar affinity for H₁-receptors from peripheral and brain tissues.1,7,10,18,19,37 In vivo, unlike sedating or first generation antihistamines, loratadine does not readily cross the blood-brain barrier and therefore does not appear to interact appreciably with H₁-receptors within the CNS.1,7,10,18,19,44 The presence of a carboxyethyl ester moiety in loratadine may limit distribution of the drug into the CNS, with a resultant decreased potential for adverse CNS effects (e.g., sedation) and anticholinergic effects compared with many other antihistamines.1,4,7,8,10,31,49 The incidence of CNS effects (e.g., sedation, impaired psychomotor performance) associated with loratadine in clinical studies is similar to that with placebo or terfenadine (no longer commercially in the US) and less than that with currently available sedating or first generation antihistamines (e.g., azatadine, chlorpheniramine, clemastine).1,7,10,18,19,37 Although the incidence of drowsiness in patients receiving the recommended 10 mg dose of loratadine is similar to that in patients receiving placebo, dose-related drowsiness may occur in patients receiving 20-40 mg of the drug.44,59 Administration of a single 10 mg dose of loratadine does not appear to impair visual-motor coordination or cause subjective CNS impairment,44,60 and administration of a single 10 or 20 mg dose44,56 or of repeated 10-mg daily doses of loratadine does not appear to impair driving performance.56 However, administration of higher than recommended doses (e.g., 20 mg daily over 4 days) can result in substantial impairment of driving performance in some individuals.56 (See Cautions: CNS Effects.)

Unlike many other currently available antihistamines, loratadine has low affinity for cholinergic receptors in vitro,51 and does not possess appreciable anticholinergic effects at doses exceeding those required for antihistaminic activity in pharmacologic studies.7,10,49 In clinical studies of individuals receiving loratadine, anticholinergic-like effects (e.g., dryness of the nose, mouth, throat, and/or lips) either did not occur or occurred with a frequency similar to that for individuals receiving placebo.1,7,10,18,19 Loratadine was a more potent inhibitor of serotonin-induced bronchospasm than terfenadine in pharmacologic studies.10 Loratadine does not exhibit any appreciable α-adrenergic blocking activity in vitro.7,10,37,51

Administration of a 10-mg dose of loratadine with alcohol44,57 or diazepam44,58 does not increase substantially the level of impairment observed with either drug alone.44,57,58 In animals, concomitant administration of large oral doses of either loratadine or terfenadine with diazepam, ethanol, hexobarbital, or phenobarbital resulted in an almost identical profile of interactions.7,32 At doses 50 times greater than their antihistamine ED₅₀, both loratadine and terfenadine potentiated the anticonvulsant effects of diazepam.7,32 At doses 80 times greater than their antihistamine ED₅₀, both antihistamines potentiated the ability of large doses of ethanol or barbiturates to induce loss of righting reflex but there was no potentiation with lower doses of ethanol or phenobarbital7,32 .

Loratadine appears to have some additional activity against inflammation mediators, but the clinical importance of this activity is unknown.7,10 Loratadine suppresses the release of histamine and leukotrienes from animal mast cells in vitro, and inhibits the release of leukotrienes (but not histamine) from human lung cell fragments.7,10 Loratadine administered orally to animals inhibits allergen- and histamine-induced bronchospasm, and suppresses changes in lung resistance and dynamic lung compliance in animals with anaphylaxis-provoked bronchospasm.10 Limited evidence suggests that loratadine has greater activity than terfenadine or astemizole (no longer commercially available in the US) in suppressing allergic or inflammatory responses in studies of individuals receiving allergenic skin prick tests or nasal challenges,10 but it is unclear to what extent these findings resulted from the antihistaminic activity of the drug,10 and additional clinical studies are required to elucidate the effects, if any, of loratadine in suppressing inflammatory mediator release in humans.7,10

Although decreased efficacy (subsensitivity, tolerance), including decreased inhibition of skin reactivity to allergen or histamine, may occur within days or weeks of initiation of therapy with first generation antihistamines,35 tolerance to the effects of loratadine has not occurred during clinical studies of patients receiving loratadine for 2-24 weeks.7,35,36,37

For further information on pharmacology of antihistamines, see the Antihistamines General Statement 4:00.

Pharmacokinetics

Absorption

Loratadine is rapidly absorbed from the GI tract following oral administration.1,10,18,19,37,38,39,42,49 The drug appears to be well absorbed following oral administration;40,41,43,44,45 however, the oral bioavailability of loratadine in humans currently is not known, although at least 85% of an orally administered dose was absorbed in animals.7,41,43 Loratadine administered to healthy adults as the syrup, conventional tablets, or orally disintegrating tablets reportedly results in plasma concentrations of the drug and its major metabolite desloratadine (descarboethoxyloratadine) that are similar for the 3 dosage forms.1,18,19 Administration of loratadine 10 mg for 10 days as orally disintegrating tablets in healthy adults results in peak plasma concentrations and areas under the plasma concentration-time curve (AUCs) that average about 6 and 11% greater than those achieved with conventional loratadine tablets.1 The manufacturer states that tablets and orally disintegrating tablets are bioequivalent with respect to the desloratadine metabolite.1 Administration of loratadine and pseudoephedrine sulfate as extended-release tablets reportedly does not affect the bioavailability of either drug substantially.18,19

Dose-independent (linear) bioavailability and pharmacokinetics of loratadine occur with increasing doses of the drug.1,7,10,18,19,38,39,41 When loratadine is administered in single doses of 10, 20, or 40 mg, the peak plasma concentration and AUC of the drug and its active metabolite desloratadine are proportional to the dose administered.7,10,38,39,41 The pharmacokinetics of loratadine and desloratadine also do not appear to be altered substantially by duration of administration;1,10,18,19,38 during a study of healthy individuals receiving 40 mg of loratadine daily for 10 days, steady-state plasma concentrations and AUCs of the drug and its metabolite were achieved by the fifth day of administration and there was little accumulation of unchanged drug.1,10,18,19,38 After either single or multiple dosing of loratadine, peak plasma concentrations of the drug usually exceed those of its active metabolite desloratadine,10,38 but AUCs of this metabolite usually exceed those of the parent drug.10,18,19

Pharmacokinetics of loratadine in children 2-12 years old are similar to those in adults;1,18,19 children 8-12 years of age receiving a single loratadine dose of 10 mg as the syrup achieve peak plasma concentrations and AUCs similar to those achieved in adults receiving this dose as oral tablets or syrup, and children 2-5 years of age receiving 5 mg of loratadine as the syrup achieve peak plasma concentrations and AUCs similar to those achieved in adults and children 8 years of age and older receiving 10 mg of the drug as oral tablets or as the syrup.1,18,19 In patients with hepatic impairment, increased plasma concentrations and AUCs of unchanged loratadine secondary to impaired metabolism of the drug can occur.1,7,10,18,19,39 Plasma concentrations and AUCs of loratadine and desloratadine are increased in adults with impaired renal function1,4,18,19,38 and in geriatric adults.1,18,19 In clinical studies, peak plasma concentrations and AUCs of loratadine were increased by about 73% and those of desloratadine were increased by about 120% in adults with impaired renal function (e.g., creatinine clearance of 30 mL/minute or less) compared with those in adults with normal renal function,1,18,19,43 and peak plasma concentrations and AUCs of loratadine and this metabolite were increased by 50% in geriatric adults (66-78 years of age) compared with younger adults.1,18,19

Food increases the extent of loratadine absorption, may increase peak plasma concentrations and AUCs of the drug, and delays time-to-peak plasma concentration of the drug and its metabolite by about 1 hour.1,18,19 Although the manufacturer states that food did not affect peak plasma concentrations of the drug or its metabolite in one single-dose study,1,18 food increased peak plasma loratadine concentrations by 80% in another study of individuals receiving a single dose of 24-hour extended-release tablets in fixed combination with pseudoephedrine sulfate,19 but did not increase substantially the peak plasma concentration of desloratadine.19 In another study, administration of a single dose of loratadine with food increased loratadine and desloratadine AUCs by about 40 and 15%, respectively. 1,18 However, in a single-dose study of adults receiving the 24-hour extended-release tablets of loratadine in fixed combination with pseudoephedrine sulfate, administration of the drug with food increased the AUC of loratadine by 120% but did not substantially affect the AUC of desloratadine.19 Food increases the AUC of loratadine administered as orally disintegrating tablets by about 48% but does not affect the AUC of desloratadine and does not affect the peak plasma concentrations of the drug or its metabolite.1 Time-to-peak plasma concentrations of loratadine and its metabolite is delayed by about 2.4 and 3.7 hours, respectively, when the orally disintegrating tablets of the drug are administered following a meal.1 Administration of loratadine orally disintegrating tablets without water increases the AUC of the drug by 26% but does not affect peak plasma loratadine concentrations;1 oral bioavailability of desloratadine is similar when orally disintegrating tablets are administered with or without water.1

Following oral administration of a single 10-mg dose of loratadine (as a capsule) in healthy adults, mean peak plasma concentrations of 4.7 and 4 ng/mL of the drug and its active metabolite were attained in about 1.5 and 3.7 hours, respectively.10 When loratadine was administered in a single 20-mg oral dose as a capsule to healthy adults, peak plasma concentrations of 10.8 and 9.9 ng/mL of loratadine or desloratadine were attained at 1 and 1.5 hours, respectively.10 Following oral administration of a single 40-mg dose of loratadine as a capsule in healthy adults, mean peak plasma concentrations of 26.1 and 16 ng/mL of the drug and its active metabolite were attained in about 1.2 and 2 hours, respectively,10 and when loratadine was administered in the same oral dose as a solution in healthy adults, peak plasma loratadine concentrations of 21 ng/mL were attained at 1 hour.10 Steady-state plasma concentrations of the drug and its active metabolite are achieved by the fifth day of administration,10,18,19 and there is little accumulation of unchanged drug.10 The AUC of loratadine is less than that of desloratadine at steady state;10,18,19 in one study, the AUC of the drug was about 23% of that of its metabolite at steady-state concentrations occurring from the fifth to the tenth day of administration.10 Following oral administration of loratadine conventional tablets at a dosage of 10 mg daily for 10 days in healthy adults, peak plasma loratadine and desloratadine concentrations occur at 1.3 and 2.5 hours, respectively.1 When loratadine is administered at this dosage as orally disintegrating tablets in healthy adults, peak plasma concentrations of the drug and its metabolite are attained at 1.3 and 2.3 hours, respectively.1 Following oral administration of loratadine capsules at a dosage of 40 mg daily for 10 days to healthy adults, peak plasma concentrations of 21.3 and 17.4 ng/mL, respectively, of loratadine and desloratadine were attained at about 1.6 and 2.9 hours on the first day; on the tenth day, peak plasma concentrations of 27.1 and 28.6 ng/mL of the drug and its active metabolite were attained at 1.4 and 3 hours, respectively.10

The magnitude and duration of the antihistaminic effect (as measured by suppression of the wheal response induced by intradermal injection of histamine) of loratadine appear to increase with increasing dosage of the drug.2,7,10,36,37,38,46,61 Following oral administration of loratadine, the antihistaminic effect of the drug is apparent within 1-4 hours,1,10,18,19,36,39 and the onset of antihistaminic action appears to correlate with the rapid absorption of loratadine and formation of desloratadine.7,10,39 The manufacturer states that when 10 mg of the drug is administered as single or multiple doses, the antihistaminic effect is maximal within 8-12 hours;1,18,19 however, in a study of patients receiving loratadine dosages of 10, 20, or 40 mg twice daily, wheal suppression was maximal at 4-6 hours after administration of the first dose.36 The manufacturer states that when 10 mg of the drug is administered in single or multiple doses, the antihistaminic effect persists for 24 hours or longer;1,18,19 however, duration of response appears to depend on the dose and duration of administration.10,36,38 In a study in healthy individuals receiving oral loratadine 10, 20, or 40 mg twice daily for 28 days, histamine-induced wheal suppression persisted for at least 12 hours after administration of the first dose of the drug and for at least 32, 36, or 48 hours after administration of the last dose of 10, 20, or 40 mg, respectively.36 In another study in healthy adults receiving single doses of loratadine, suppression of histamine-induced wheal response persisted for 12 hours following oral administration of a 10 mg dose and for 48 hours after a 40 or 80 mg dose.2,10,38,46,61

Although a therapeutic range for plasma loratadine concentrations has not been established, the manufacturer states that following oral administration of a therapeutic dose of loratadine, the expected plasma concentration of unchanged drug is 2.5-100 ng/mL, and that of desloratadine is 0.5-100 ng/mL.18,19

Distribution

Distribution of loratadine and its metabolites into human body tissues and fluids has not been determined.10 Large clearance values following oral administration of loratadine suggest extensive presystemic metabolism and/or tissue distribution of the drug in humans.7,10,41,42 Neither loratadine nor its metabolites appear to cross the blood-brain barrier appreciably in animals.1,18,19

At expected plasma concentrations of the drug and its metabolite following administration of a therapeutic dose in healthy adults, loratadine and desloratadine are about 97-99 and 73-77% bound, respectively, to plasma proteins.7,10,18,19,39,40

Loratadine and its active metabolite desloratadine are distributed into breast milk in concentrations that are equivalent to plasma concentrations.1,7,10,18,19,40 The AUCs of the drug and this metabolite in breast milk are about 117 and 85%, respectively, of maternal plasma AUCs;1,10,18,19,40 however, the total amount of loratadine and its active metabolite excreted into breast milk is minimal.7,10 In one study, about 0.03% (11.7 mcg) of a single 40-mg oral dose of loratadine was excreted into breast milk as loratadine and desloratadine over 48 hours.1,10,18,19,40

Elimination

Plasma concentrations of loratadine and desloratadine appear to decline in a biphasic manner.7,10,37,41,42 In healthy adults receiving either single 10-, 20-, or 40-mg doses or a daily dosage of 40 mg of the drug, the mean distribution half-life of unchanged loratadine was about 1-2 hours,7,10,37,41,42 and the mean elimination half-life was 8-15 hours;1,7,10,18,19,37,41,42,44,49 the mean distribution half-life of desloratadine was 2-4 hours,7,10,41,42 and the mean elimination half-life was about 17-28 hours.1,7,10,18,19,41,42,44,49 Plasma clearance of loratadine is high after oral administration, probably secondary to extensive first-pass metabolism and tissue distribution.7,41 Like the elimination half-life, oral clearance of loratadine does not vary greatly with dose;7 apparent clearance after oral administration of a single 20- or 40-mg dose of the drug in healthy adults was 202 or 142 mL/minute per kg (12.1 or 8.5 L/hour per kg), respectively.7,10,41

Loratadine undergoes extensive first-pass metabolism, and is metabolized in the liver by the cytochrome P-450 (CYP) microsomal enzyme system, principally by hydrolysis of the carbamate moiety to the active metabolite desloratadine.1,18,19,39,41,44,49,50 Results of in vitro studies using human liver microsomes indicate that metabolism of loratadine is mediated principally by the isoenzyme 3A4 (CYP3A4) and to a lesser extent by CYP2D6.1,39 In the presence of a CYP3A4 inhibitor (e.g., ketoconazole), loratadine is principally metabolized to desloratadine by the CYP2D6 isoenzyme.1,39 Concomitant administration of the drug with either a CYP3A4 inhibitor (e.g., ketoconazole, erythromycin) or a CYP3A4 and CYP2D6 inhibitor (e.g., cimetidine) is associated with substantially increased plasma concentrations of unchanged drug in healthy individuals.1,18,19 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

In patients with hepatic impairment, the half-life of loratadine and desloratadine may be prolonged.1,7,10,18,19,39 In patients with chronic alcoholic liver disease, the elimination half-life of loratadine and desloratadine generally increases with increasing severity of liver disease,1,10,18,19 but usually appears to be within the range (e.g., 3-20 and 9-92 hours, respectively) reported for healthy individuals.1,10,18,19,39 In patients with impaired renal function, the half-lives of the drug and its active metabolite do not appear to be prolonged compared with individuals with normal renal function.1,4,18,19,38

Desloratadine is pharmacologically active,7,10,43,44,45,49 and also is extensively metabolized by hydroxylation10,39,43,45,49 and undergoes conjugation.7,45 Limited evidence from animal studies indicates that desloratadine may have about 4 times the antihistaminic activity of the parent drug on a mg-for-mg basis,7 but the conjugated metabolites of desloratadine are assumed to have minimal activity.7

After 10 days of daily administration of loratadine, about 80% of the drug is excreted as metabolic products equally distributed in urine and feces.1,18,19 After administration of a single 40-mg dose of ¹⁴C-loratadine as an oral solution in healthy individuals, approximately 40% of the radiolabeled dose was recovered in the urine over 7 days.43 High-performance liquid chromatography (HPLC) analysis of urine radioactivity identified only small fractions of loratadine- and desloratadine-associated radioactivity, and a larger fraction that was tentatively identified as hydroxydesloratadine.10,45 Most plasma radioactivity was attributed to conjugates of desloratadine metabolites,10,45 and plasma radioactivity cleared with a half-life of 46 hours,7,10,39,45 a rate similar to the excretion of radioactivity in urine.10,45

Plasma drug clearance may be decreased and the half-life prolonged in geriatric individuals,39,49 but differences in pharmacokinetics between geriatric and younger adults do not appear to be substantial, and some clinicians state such differences are unlikely to be clinically important.39,49 In healthy geriatric individuals, the mean elimination half-life of loratadine is increased to 18.2 hours (range: 6.7-37 hours), but that of desloratadine is decreased to 17.5 hours (range: 11-38 hours).1,18,19,49

In patients with impaired renal function (e.g., creatinine clearance of 30 mL/minute or less) the mean elimination half-lives of loratadine and its active metabolite desloratadine appear to be similar to those in individuals with normal renal function.1,4,10,18,19,39,43,50 Neither loratadine nor desloratadine is substantially removed by hemodialysis.1,7,10,18,19,39,43

Chemistry and Stability

Chemistry

Loratadine is a tricyclic antihistamine.1,7,18,19 The drug is a derivative of azatadine, 7,10,31,37,44 and is related structurally to cyproheptadine.15,31 Loratadine differs from azatadine by the presence of a carboxyethyl ester moiety on the piperidine ring and an 8-chloro group on the benzocycloheptapyridine tricyclic ring structure.4,8,31 Conversion of the basic tertiary amino function of azatadine to a neutral carbamate results in compounds, including loratadine, that are less basic and more polar than the parent drug, decreasing their distribution into the CNS.7,10,31 Although the ethyl carbamate derivative has about 1/80th the potency of azatadine,31 the addition of an 8-chloro group to the tricyclic ring of this compound to form loratadine increases its potency fourfold, and substantially increases its duration of action.7,10,31 Loratadine occurs as a white to off-white powder and is insoluble in water but very soluble in alcohol, acetone, and chloroform.1,18,19

The orally disintegrating loratadine tablets differ from the conventional tablet formulation;1 both dosage forms contain 10 mg of the drug in each tablet, and are administered orally, but the orally disintegrating tablets are flavored and disintegrate within seconds after placement on the tongue, allowing the tablet contents to be swallowed with or without water.1,71,74 The fixed-combination tablets formulated for 12-hour dosing contain 5 mg of loratadine and 60 mg of pseudoephedrine sulfate in an immediate-release outer shell and 60 mg of pseudoephedrine sulfate in an extended-release matrix core that slowly releases the drug18 whereas the fixed-combination tablets formulated for 24-hour dosing contain 10 mg of loratadine in an immediate-release outer shell and 240 mg of pseudoephedrine sulfate in an extended-release matrix core that slowly releases the drug.19,20

Stability

Loratadine syrup, tablets, orally disintegrating tablets, and fixed-combination loratadine and pseudoephedrine sulfate extended-release tablets should be stored in tight, light-resistant containers.1,18,19 Loratadine tablets should be stored at 2-30°C,67 and the syrup and orally disintegrating tablets, should be stored at 2-25°C.1,18,71,72 The fixed-combination extended-release tablets formulated for 12- or 24-hour dosing should be stored at 15-25°C.19,70,73,75

Loratadine preparations commercially available in blister packages for individual and institutional use should be stored in a dry place and protected from excessive moisture;1,18,19,67,71,75 the fixed-combination extended-release tablets formulated for 24-hour dosing and commercially available in unit dose blister packages for institutional use also should be protected from light.19,70 Loratadine orally disintegrating tablets commercially available in blister packages should be used within 6 months of opening the laminated foil pouch enclosing each blister card, and each tablet should be used immediately after opening an individual blister;1,71 individual orally disintegrating tablets that are not used immediately after opening the blister should be discarded.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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