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Patients and parents/caregivers of pediatric patients taking Allegra Tablets, Allegra ODT or Allegra Oral Suspension should receive the following information:

Allegra Tablets, Allegra ODT or Allegra Oral Suspension are prescribed for the relief of symptoms of seasonal allergic rhinitis or for the relief of symptoms of chronic idiopathic urticaria (hives). Patients should be instructed to take Allegra only as prescribed. Do not exceed the recommended dose. If any untoward effects occur while taking Allegra discontinue use and consult a doctor.

The products should not be used by patients who are hypersensitive to any of the ingredients.

These products should be used in pregnancy or lactation only if the potential benefit justifies the potential risk to the fetus or nursing infant.

Patients and parents/caregivers of pediatric patients should also be advised to store the medication in a tightly closed container in a cool, dry place, away from small children.

For Allegra Tablets: Patients should be advised to take the Allegra Tablets with water.

For Allegra ODT: For Allegra ODT, patients should be advised to take their dose on an empty stomach. Allegra ODT should be allowed to disintegrate on the tongue, followed by swallowing with or without water. Allegra ODT is not intended to be chewed. Allegra ODT should be stored in its original blister package. Allegra ODT should not be removed from the original blister package until the time of administration.

Phenylketonurics: Allegra ODT contains phenylalanine, a component of aspartame. Each 30-mg Allegra ODT contains 5.3 mg phenylalanine. Allegra products other than Allegra ODT do not contain phenylalanine.

For Allegra Oral Suspension: Patients and parents/caregivers of pediatric patients should be advised to shake the Allegra Oral Suspension bottle well, before each use.

Rev.

sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

Allegra ODT manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

©2006 sanofi-aventis U.S. LLC

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Allegra Oral Suspension (fexofenadine hydrochloride, 30 mg/5mL (6 mg/mL)) is available in amber PET bottles containing 30 mL (NDC 0088-1097-10) and 300 mL (NDC 0088-1097-20) of suspension.

Store Allegra Oral Suspension at controlled room temperature 20–25°C (68–77°F). (See USP Controlled Room Temperature).

Shake bottle well, before each use.

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Allegra ODT 30 mg Orally Disintegrating Tablets are available in aluminum-foil blister packs of 60 (NDC 0088-1113-30).

Each Allegra ODT is white, flat-faced, ½-inch round shaped with beveled edges and debossed with a scripted “e” on one side and “311AV” on the other side.

Store Allegra ODT at controlled room temperature 20–25°C (68–77°F). (See USP Controlled Room Temperature). Foil-backed blister packs containing Allegra ODT should be protected from moisture. Allegra ODT should not be removed from the original blister package until the time of administration.

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Allegra 30 mg tablets are available in: high-density polyethylene (HDPE) bottles of 100 (NDC 0088-1106-47) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal and HDPE bottles of 500 (NDC 0088-1106-55) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal.

Allegra 60 mg tablets are available in: HDPE bottles of 100 (NDC 0088-1107-47) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal; HDPE bottles of 500 (NDC 0088-1107-55) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal; and aluminum foil-backed clear blister packs of 100 (NDC 0088-1107-49).

Allegra 180 mg tablets are available in: HDPE bottles of 100 (NDC 0088-1109-47) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal and HDPE bottles of 500 (NDC 0088-1109-55) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal.

Allegra Tablets are coated with a peach colored film coating. Tablets have the following unique shape and identifiers: 30 mg tablets are round, bi-convex and have 03 on one side and a scripted “e” on the other; 60 mg tablets are oval, bi-convex and have 06 on one side and a scripted “e” on the other; and 180 mg tablets are oblong, bi-convex and have 018 on one side and a scripted “e” on the other.

Store Allegra Tablets at controlled room temperature 20–25°C (68–77°F). (See USP Controlled Room Temperature). Foil-backed blister packs containing Allegra Tablets should be protected from excessive moisture.

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Two 4-week, multicenter, randomized, double-blind, placebo-controlled clinical trials compared four different doses of 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 fexofenadine hydrochloride doses of ≥60 mg twice daily. However, no additional benefit of the 120 or 240 mg 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 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), 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 fexofenadine hydrochloride180 mg than with placebo. Improvement was demonstrated within 1 day of treatment with fexofenadine hydrochloride 180 mg and was maintained over the entire 4-week treatment period. There were no significant differences in the effect of fexofenadine hydrochloride across subgroups of subjects defined by gender, age, and race.

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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), 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 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), 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 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 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 60 mg capsules, and in 1 clinical trial conducted with Allegra-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 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.

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Fexofenadine hydrochloride, the active ingredient of Allegra Tablets, Allegra ODT and Allegra Oral Suspension, is a histamine H1-receptor antagonist with the chemical name (±)-4-[1 hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl benzeneacetic acid hydrochloride.

The molecular weight is 538.13 and the empirical formula is C32H39NO4•HCl.

Fexofenadine hydrochloride is a white to off-white crystalline powder. It is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane. Fexofenadine hydrochloride is a racemate and exists as a zwitterion in aqueous media at physiological pH.

Allegra is formulated as a tablet for oral administration. Each tablet contains 30, 60, or 180 mg fexofenadine hydrochloride (depending on the dosage strength) and the following excipients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The aqueous tablet film coating is made from hypromellose, iron oxide blends, polyethylene glycol, povidone, silicone dioxide, and titanium dioxide.

Allegra ODT is formulated for rapid disintegration in the mouth immediately following administration. Each orally disintegrating tablet contains 30 mg fexofenadine hydrochloride and the following excipients: citric acid anhydrous, crospovidone, magnesium stearate, mannitol, methacrylate copolymer, microcrystalline cellulose, povidone K-30, sodium bicarbonate, sodium starch glycolate, aspartame, natural and artificial orange flavor, artificial cream flavor, and alcohol anhydrous; the alcohol is predominantly removed during the manufacturing process.

Allegra Oral Suspension, a white uniform suspension, contains 6 mg fexofenadine hydrochloride per mL and the following excipients: polypropylene glycol, edetate disodium, propylparaben, butylparaben, xanthan gum, poloxamer 407, titanium dioxide, sodium phosphate monobasic monohydrate, sodium phosphate dibasic heptahydrate, artificial raspberry cream flavor, sucrose, xylitol and purified water.

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Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of fexofenadine was assessed using terfenadine studies with adequate fexofenadine exposure (based on plasma area-under-the-concentration vs. time [AUC] values). No evidence of carcinogenicity was observed in an 18-month study in mice and in a 24-month study in rats at oral doses up to 150 mg/kg of terfenadine (which led to fexofenadine exposures that were approximately 3 and 5 times the exposure at the maximum recommended daily oral dose of fexofenadine hydrochloride in adults [180 mg] and children [60 mg] respectively).

In in vitro (Bacterial Reverse Mutation, CHO/HGPRT Forward Mutation, and Rat Lymphocyte Chromosomal Aberration assays) and in vivo (Mouse Bone Marrow Micronucleus assay) tests, fexofenadine hydrochloride revealed no evidence of mutagenicity.

In rat fertility studies, dose-related reductions in implants and increases in postimplantation losses were observed at an oral dose of 150 mg/kg of terfenadine (which led to fexofenadine exposures that were approximately 3 times the exposure at the maximum recommended human daily oral dose of 180 mg of fexofenadine hydrochloride based on comparison of AUCs). In mice, fexofenadine hydrochloride produced no effect on male or female fertility at average oral doses up to 4438 mg/kg (which led to fexofenadine exposures that were approximately 13 times the exposure at the maximum recommended human daily oral dose of 180 mg of fexofenadine hydrochloride in adults based on comparison of AUCs).

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The pharmacokinetics of 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 rapidly 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. 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 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: Fexofenadine hydrochloride was rapidly absorbed following single-dose oral administration of Allegra ODT 30 mg to healthy adult subjects. The mean maximum plasma concentration (Cmax) was 88.0 ng/mL and occurred at approximately 2.0 hours (Tmax) following oral administration. Allegra ODT 30 mg tablets are bioequivalent to the 30 mg Allegra Tablets. The administrationof Allegra 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 ODT should be taken on an empty stomach. The bioavailability of Allegra ODT was comparable whether given with or without water.

Allegra Oral Suspension: A dose of 5 mL of Allegra Oral Suspension containing 30 mg of fexofenadine hydrochloride is bioequivalent to a 30 mg dose of Allegra Tablets. Following oral administration of a 30 mg dose of Allegra Oral Suspension to healthy adult subjects, the mean Cmax was 118.0 ng/mL and occurred at approximately 1.0 hour. The administration of 30 mg Allegra 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
Fexofenadine hydrochloride is 60% to 70% bound to plasma proteins, primarily albumin and α1-acid glycoprotein.

Metabolism
Approximately 5% of the total dose of 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] fexofenadine hydrochloride dose in the feces and urine, respectively. Because the absolute bioavailability of 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 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.

Hepatically Impaired. The pharmacokinetics of fexofenadine hydrochloride in subjects with hepatic disease 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 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 fexofenadine hydrochloride.

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Wheal and Flare. Human histamine skin wheal and flare studies in adults following single and twice daily doses of 20 and 40 mg 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.

Effects on QTc. In dogs (30 mg/kg/orally twice daily for 5 days) and rabbits (10 mg/kg, intravenously over 1 hour), 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 × 10-5 M of fexofenadine.

No statistically significant increase in mean QTc interval compared to placebo was observed in 714 adult subjects with seasonal allergic rhinitis given 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 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 fexofenadine hydrochloride as an oral solution at doses up to 400 mg twice daily for 6 days, or in 230 healthy adult subjects given 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 fexofenadine hydrochloride 180 mg once daily (n = 163) and those treated with placebo (n = 91) for 4 weeks.

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