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Allegra

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Allegra

CLINICAL PHARMACOLOGY

Mechanism of Action

ALLEGRA (fexofenadine hydrochloride), the major active metabolite of terfenadine, is an antihistamine with selective H1-receptor antagonist activity. Both enantiomers of ALLEGRA (fexofenadine hydrochloride) displayed approximately equipotent antihistaminic effects. ALLEGRA (fexofenadine hydrochloride) inhibited antigen-induced bronchospasm in sensitized guinea pigs and histamine release from peritoneal mast cells in rats. The clinical significance of these findings is unknown. In laboratory animals, no anticholinergic or alpha1-adrenergic blocking effects were observed. Moreover, no sedative or other central nervous system effects were observed. Radiolabeled tissue distribution studies in rats indicated that fexofenadine does not cross the blood-brain barrier.

Pharmacodynamics

Wheal and Flare: Human histamine skin wheal and flare studies in adults following single and twice daily doses of 20 and 40 mg ALLEGRA (fexofenadine hydrochloride) demonstrated that the drug exhibits an antihistamine effect by 1 hour, achieves maximum effect at 2 to 3 hours, and an effect is still seen at 12 hours. There was no evidence of tolerance to these effects after 28 days of dosing. The clinical significance of these observations is unknown.

Histamine skin wheal and flare studies in 7 to 12 year old subjects showed that following a single dose of 30 or 60 mg, antihistamine effect was observed at 1 hour and reached a maximum by 3 hours. Greater than 49% inhibition of wheal area, and 74% inhibition of flare area were maintained for 8 hours following the 30 and 60 mg dose.

No statistically significant increase in mean QTc interval compared to placebo was observed in 714 adult subjects with seasonal allergic rhinitis given ALLEGRA (fexofenadine hydrochloride) capsules in doses of 60 to 240 mg twice daily for 2 weeks. Pediatric subjects from 2 placebo- controlled trials (n=855) treated with up to 60 mg ALLEGRA (fexofenadine hydrochloride) twice daily demonstrated no significant treatment- or dose-related increases in QTc. In addition, no statistically significant increase in mean QTc interval compared to placebo was observed in 40 healthy adult subjects given ALLEGRA (fexofenadine hydrochloride) as an oral solution at doses up to 400 mg twice daily for 6 days, or in 230 healthy adult subjects given ALLEGRA (fexofenadine hydrochloride) 240 mg once daily for 1 year. In subjects with chronic idiopathic urticaria, there were no clinically relevant differences for any ECG intervals, including QTc, between those treated with ALLEGRA (fexofenadine hydrochloride) 180 mg once daily (n = 163) and those treated with placebo (n = 91) for 4 weeks.

Pharmacokinetics

The pharmacokinetics of ALLEGRA (fexofenadine hydrochloride) in subjects with seasonal allergic rhinitis and subjects with chronic urticaria were similar to those in healthy subjects.

Absorption

ALLEGRA tablets: Fexofenadine hydrochloride was absorbed following oral administration of a single dose of two 60 mg capsules to healthy male subjects with a mean time to maximum plasma concentration occurring at 2.6 hours post-dose. After administration of a single 60 mg capsule to healthy adult subjects, the mean maximum plasma concentration (Cmax) was 131 ng/mL. Following single dose oral administrations of either the 60 and 180 mg tablet to healthy adult male subjects, mean Cmax were 142 and 494 ng/mL, respectively. The tablet formulations are bioequivalent to the capsule when administered at equal doses. ALLEGRA (fexofenadine hydrochloride) pharmacokinetics are linear for oral doses up to a total daily dose of 240 mg (120 mg twice daily). The administration of the 60 mg capsule contents mixed with applesauce did not have a significant effect on the pharmacokinetics of fexofenadine in adults. Co-administration of 180 mg ALLEGRA (fexofenadine hydrochloride) tablet with a high fat meal decreased the mean area under the curve (AUC) and (Cmax) of fexofenadine by 21 and 20% respectively.

ALLEGRA ODT: ALLEGRA (Fexofenadine hydrochloride) was absorbed following single-dose oral administration of ALLEGRA (fexofenadine hcl) ODT 30 mg to healthy adult subjects with a mean time to maximum plasma concentration occurring at approximately 2.0 hours post-dose. After single-dose administration of ALLEGRA (fexofenadine hcl) 30 mg ODT to healthy adult subjects, the mean maximum plasma concentration (Cmax) was 88.0 ng/mL. ALLEGRA (fexofenadine hcl) ODT 30 mg tablets are bioequivalent to the 30 mg ALLEGRA (fexofenadine hcl) tablets. The administration of ALLEGRA (fexofenadine hcl) ODT 30 mg with a high-fat meal decreased the AUC and Cmax by approximately 40% and 60% respectively and a 2-hour delay in the time to peak exposure (Tmax) was observed. ALLEGRA (fexofenadine hcl) ODT should be taken on an empty stomach. The bioavailability of ALLEGRA (fexofenadine hcl) ODT was comparable whether given with or without water [see DOSAGE AND ADMINISTRATION].

ALLEGRA (fexofenadine hcl) oral suspension: A dose of 5 mL of ALLEGRA oral suspension containing 30 mg of ALLEGRA (fexofenadine hydrochloride) is bioequivalent to a 30 mg dose of ALLEGRA (fexofenadine hcl) tablets. Following oral administration of a 30 mg dose of ALLEGRA (fexofenadine hcl) oral suspension to healthy adult subjects, the mean Cmax was 118 ng/mL and occurred at approximately 1 hour. The administration of 30 mg ALLEGRA (fexofenadine hcl) oral suspension with a high fat meal decreased the AUC and the mean Cmax by approximately 30 and 47%, respectively in healthy adult subjects.

Distribution

ALLEGRA (fexofenadine hydrochloride) is 60% to 70% bound to plasma proteins, primarily albumin and α 1-acid glycoprotein.

Metabolism

Approximately 5% of the total dose of ALLEGRA (fexofenadine hydrochloride) was eliminated by hepatic metabolism.

Elimination

The mean elimination half-life of fexofenadine was 14.4 hours following administration of 60 mg twice daily in healthy adult subjects.

Human mass balance studies documented a recovery of approximately 80% and 11% of the [14C] ALLEGRA (fexofenadine hydrochloride) dose in the feces and urine, respectively. Because the absolute bioavailability of ALLEGRA (fexofenadine hydrochloride) has not been established, it is unknown if the fecal component represents primarily unabsorbed drug or is the result of biliary excretion.

Special Populations

Pharmacokinetics in renally and hepatically impaired subjects and geriatric subjects, obtained after a single dose of 80 mg ALLEGRA (fexofenadine hydrochloride), were compared to those from healthy subjects in a separate study of similar design.

Renally Impaired

In subjects with mild to moderate (creatinine clearance 41-80 mL/min) and severe (creatinine clearance 11-40 mL/min) renal impairment, peak plasma concentrations of fexofenadine were 87% and 111% greater, respectively, and mean elimination half-lives were 59% and 72% longer, respectively, than observed in healthy subjects. Peak plasma concentrations in subjects on dialysis (creatinine clearance ≤ 10 mL/min) were 82% greater and half-life was 31% longer than observed in healthy subjects. Based on increases in bioavailability and half-life, a dose of 60 mg once daily is recommended as the starting dose in adult patients with decreased renal function. For pediatric patients with decreased renal function, the recommended starting dose of fexofenadine is 30 mg once daily for patients 2 to 11 years of age and 15 mg once daily for patients 6 months to less than 2 years of age [see DOSAGE AND ADMINISTRATION].

Hepatically Impaired

The pharmacokinetics of ALLEGRA (fexofenadine hydrochloride) in subjects with hepatic impairment did not differ substantially from that observed in healthy subjects.

Geriatric Subjects

In older subjects ( ≥ 65 years old), peak plasma levels of fexofenadine were 99% greater than those observed in younger subjects ( < 65 years old). Mean fexofenadine elimination half-lives were similar to those observed in younger subjects.

Pediatric Subjects

A population pharmacokinetic analysis was performed with data from 77 pediatric subjects (6 months to 12 years of age) with allergic rhinitis and 136 adult subjects. The individual apparent oral clearance estimates of fexofenadine were on average 44% and 36% lower in pediatric subjects 6 to 12 years (n=14) and 2 to 5 years of age (n=21), respectively, compared to adult subjects.

Administration of a 15 mg dose of ALLEGRA (fexofenadine hydrochloride) to pediatric subjects 6 months to less than 2 years of age and a 30 mg dose to pediatric subjects 2 to 11 years of age produced exposures comparable to those seen with a dose of 60 mg administered to adults.

Effect of Gender

Across several trials, no clinically significant gender-related differences were observed in the pharmacokinetics of ALLEGRA (fexofenadine hydrochloride).

Animal Toxicology and/or Pharmacology

In dogs (30 mg/kg/orally twice daily for 5 days) and rabbits (10 mg/kg, intravenously over 1 hour), ALLEGRA (fexofenadine hydrochloride) did not prolong QTc. In dogs, the plasma fexofenadine concentration was approximately 9 times the therapeutic plasma concentrations in adults receiving the maximum recommended human daily oral dose of 180 mg. In rabbits, the plasma fexofenadine concentration was approximately 20 times the therapeutic plasma concentration in adults receiving the maximum recommended human daily oral dose of 180 mg. No effect was observed on calcium channel current, delayed K+ channel current, or action potential duration in guinea pig myocytes, or on the delayed rectifier K+ channel cloned from human heart at concentrations up to 1 x 10-5 M of fexofenadine.

Clinical Studies

Seasonal Allergic Rhinitis

Adults: In three 2-week, multicenter, randomized, double-blind, placebo-controlled trials in subjects 12 to 68 years of age with seasonal allergic rhinitis (n=1634), ALLEGRA (fexofenadine hydrochloride) 60 mg twice daily significantly reduced total symptom scores (the sum of the individual scores for sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo. Statistically significant reductions in symptom scores were observed following the first 60 mg dose, with the effect maintained throughout the 12-hour interval. In these studies, there was no additional reduction in total symptom scores with higher doses of ALLEGRA (fexofenadine hydrochloride) up to 240 mg twice daily.

In one 2-week, multicenter, randomized, double-blind clinical trial in subjects 12 to 65 years of age with seasonal allergic rhinitis (n=863), ALLEGRA (fexofenadine hydrochloride) 180 mg once daily significantly reduced total symptom scores (the sum of the individual scores for sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo. Although the number of subjects in some of the subgroups was small, there were no significant differences in the effect of ALLEGRA (fexofenadine hydrochloride) across subgroups of subjects defined by gender, age, and race. Onset of action for reduction in total symptom scores, excluding nasal congestion, was observed at 60 minutes compared to placebo following a single 60 mg ALLEGRA (fexofenadine hydrochloride) dose administered to subjects with seasonal allergic rhinitis who were exposed to ragweed pollen in an environmental exposure unit. In 1 clinical trial conducted with ALLEGRA (fexofenadine hcl) 60 mg capsules, and in 1 clinical trial conducted with ALLEGRA (fexofenadine hcl) -D 12 Hour extended release tablets, onset of action was seen within 1 to 3 hours.

Pediatrics: Two 2-week, multicenter, randomized, placebo-controlled, double-blind trials in 877 pediatric subjects 6 to 11 years of age with seasonal allergic rhinitis were conducted at doses of 15, 30, and 60 mg (tablets) twice daily. In 1 of these 2 studies, conducted in 411 pediatric subjects, all 3 doses of ALLEGRA (fexofenadine hydrochloride) significantly reduced total symptom scores (the sum of the individual scores for sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo, however, a dose-response relationship was not seen. The 60 mg twice daily dose did not provide any additional benefit over the 30 mg twice daily dose in pediatric subjects 6 to 11 years of age.

Administration of a 30 mg dose to pediatric subjects 2 to 11 years of age produced exposures comparable to those seen with a dose of 60 mg administered to adults. [See CLINICAL PHARMACOLOGY].

Chronic Idiopathic Urticaria

Two 4-week, multicenter, randomized, double-blind, placebo-controlled clinical trials compared four different doses of ALLEGRA (fexofenadine hydrochloride) tablet (20, 60, 120, and 240 mg twice daily) to placebo in subjects aged 12 to 70 years with chronic idiopathic urticaria (n=726). Efficacy was demonstrated by a significant reduction in mean pruritus scores (MPS), mean number of wheals (MNW), and mean total symptom scores (MTSS, the sum of the MPS and MNW score). Although all 4 doses were significantly superior to placebo, symptom reduction was greater and efficacy was maintained over the entire 4-week treatment period with ALLEGRA (fexofenadine hydrochloride) doses of ≥ 60 mg twice daily. However, no additional benefit of the 120 or 240 mg ALLEGRA (fexofenadine hydrochloride) twice daily dose was seen over the 60 mg twice daily dose in reducing symptom scores. There were no significant differences in the effect of ALLEGRA (fexofenadine hydrochloride) across subgroups of subjects defined by gender, age, weight, and race.

In one 4-week, multicenter, randomized, double-blind, placebo-controlled clinical trial in subjects 12 years of age and older with chronic idiopathic urticaria (n=259), ALLEGRA (fexofenadine hydrochloride) 180 mg once daily significantly reduced the mean number of wheals (MNW), the mean pruritus score (MPS), and the mean total symptom score (MTSS, the sum of the MPS and MNW scores). Similar reductions were observed for mean number of wheals and mean pruritus score at the end of the 24-hour dosing interval. Symptom reduction was greater with ALLEGRA (fexofenadine hydrochloride) 180 mg than with placebo. Improvement was demonstrated within 1 day of treatment with ALLEGRA (fexofenadine hydrochloride) 180 mg and was maintained over the entire 4­week treatment period. There were no significant differences in the effect of ALLEGRA (fexofenadine hydrochloride) across subgroups of subjects defined by gender, age, and race.

Last reviewed on RxList: 11/1/2010
This monograph has been modified to include the generic and brand name in many instances.

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