allegra (fexofenadine hydrochloridetablet, film coated 
allegra (fexofenadine hydrochloridesuspension 

DESCRIPTION

Fexofenadine hydrochloride, the active ingredient of ALLEGRA tablets 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. It has the following chemical structure

Image from Drug Label Content

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 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.

CLINICAL PHARMACOLOGY

Mechanism of Action

Fexofenadine hydrochloride, the major active metabolite of terfenadine, is an antihistamine with selective peripheral H1-receptor antagonist activity. Both enantiomers of fexofenadine hydrochloride displayed approximately equipotent antihistaminic effects. 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.

PHARMACOKINETICS

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

Absorption

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 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.

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 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 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 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 fexofenadine 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.

Pharmacodynamics

Wheal and Flare

Human histamine skin wheal and flare studies 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 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 subjects given fexofenadine hydrochloride as an oral solution at doses up to 400 mg twice daily for 6 days, or in 230 healthy 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.

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), 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 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. (see CLINICAL PHARMACOLOGY).

Chronic Idiopathic Urticaria

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.

INDICATIONS AND USAGE

Seasonal Allergic Rhinitis

ALLEGRA tablets are indicated for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older.

ALLEGRA Oral Suspension is indicated for the relief of symptoms associated with seasonal allergic rhinitis in children 2 to 11 years of age.

Symptoms treated effectively were sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes.

Chronic Idiopathic Urticaria

ALLEGRA tablets are indicated for treatment of uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older.

ALLEGRA Oral Suspension is indicated for treatment of uncomplicated skin manifestations of chronic idiopathic urticaria in children 6 months to 11 years of age.

Fexofenadine hydrochloride significantly reduces pruritus and the number of wheals.

CONTRAINDICATIONS

ALLEGRA tablets and ALLEGRA Oral Suspension are contraindicated in patients with known hypersensitivity to any of the ingredients.

PRECAUTIONS

INFORMATION FOR PATIENTS

Patients and parents/caregivers of pediatric patients taking ALLEGRA tablets or suspension should receive the following information:

ALLEGRA tablets or 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 should be advised to take the ALLEGRA tablets with water.

Patients and parents/caregivers of pediatric patients should be advised to shake the ALLEGRA Oral suspension bottle well, before each use.

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.

Drug Interaction with Erythromycin and Ketoconazole

Fexofenadine has been shown to exhibit minimal (ca. 5%) metabolism. However, co–administration of fexofenadine hydrochloride with either ketoconazole or erythromycin led to increased plasma concentrations of fexofenadine. Fexofenadine had no effect on the pharmacokinetics of either erythromycin or ketoconazole. In 2 separate studies, fexofenadine hydrochloride 120 mg twice daily (240 mg total daily dose) was co-administered with either erythromycin 500 mg every 8 hours or ketoconazole 400 mg once daily under steady-state conditions to healthy subjects (n=24, each study). No differences in adverse events or QTc interval were observed when subjects were administered fexofenadine hydrochloride alone or in combination with either erythromycin or ketoconazole. The findings of these studies are summarized in the following table

Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy subjects (n=24)
Concomitant Drug CmaxSS
(Peak plasma concentration)
AUCss(0–12h)
(Extent of systemic exposure)
Erythromycin
(500 mg every 8 hrs)
+82% +109%
  
Ketoconazole
(400 mg once daily)
+135% +164%

The changes in plasma levels were within the range of plasma levels achieved in adequate and well-controlled clinical trials.

The mechanism of these interactions has been evaluated in in vitro, in situ, and in vivo animal models. These studies indicate that ketoconazole or erythromycin co-administration enhances fexofenadine gastrointestinal absorption. This observed increase in the bioavailability of fexofenadine may be due to transport-related effects, such as p-glycoprotein. In vivo animal studies also suggest that in addition to enhancing absorption, ketoconazole decreases fexofenadine gastrointestinal secretion, while erythromycin may also decrease biliary excretion.

Drug Interactions with Antacids

Administration of 120 mg of fexofenadine hydrochloride (2 x 60 mg capsule) within 15 minutes of an aluminum and magnesium containing antacid (Maalox®) decreased fexofenadine AUC by 41% and Cmax by 43%. ALLEGRA should not be taken closely in time with aluminum and magnesium containing antacids.

Interactions with Fruit Juices

Fruit juices such as grapefruit, orange and apple may reduce the bioavailability and exposure of fexofenadine. This is based on the results from 3 clinical studies using histamine induced skin wheals and flares coupled with population pharmacokinetic analysis. The size of wheal and flare were significantly larger when fexofenadine hydrochloride was administered with either grapefruit or orange juices compared to water. Based on the literature reports, the same effects may be extrapolated to other fruit juices such as apple juice. The clinical significance of these observations is unknown. In addition, based on the population pharmacokinetics analysis of the combined data from grapefruit and orange juices studies with the data from a bioequivalence study, the bioavailability of fexofenadine was reduced by 36%. Therefore, to maximize the effects of fexofenadine, it is recommended that ALLEGRA tablets should be taken with water (see Pharmacokinetics and DOSAGE AND ADMINISTRATION).

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 based on comparison of AUCs).

PREGNANCY

Teratogenic Effects

Category C. There was no evidence of teratogenicity in rats or rabbits at oral doses of terfenadine up to 300 mg/kg (which led to fexofenadine exposures that were approximately 4 and 30 times, respectively, the exposure at the maximum recommended human daily oral dose of 180 mg of fexofenadine hydrochloride based on comparison of AUCs).

In mice, no adverse effects and no teratogenic effects during gestation were observed with fexofenadine hydrochloride at oral doses up to 3730 mg/kg (which led to fexofenadine exposures that were approximately 15 times the exposure at the maximum recommended human daily oral dose of 180 mg of fexofenadine hydrochloride based on comparison of AUCs).

There are no adequate and well controlled studies in pregnant women. ALLEGRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Dose-related decreases in pup weight gain and survival were observed in rats exposed to 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).

NURSING MOTHERS

It is not known if fexofenadine is excreted in human milk. There are no adequate and well-controlled studies in women during lactation. Because many drugs are excreted in human milk, caution should be exercised when ALLEGRA is administered to a nursing woman.

PEDIATRIC USE

The recommended doses in pediatric patients 6 months to 11 years of age are based on cross-study comparison of the pharmacokinetics of fexofenadine in adults and pediatric subjects and on the safety profile of fexofenadine hydrochloride in both adult and pediatric subjects at doses equal to or higher than the recommended doses.

The safety of ALLEGRA at a dose of 30 mg twice daily has been demonstrated in 438 pediatric subjects 6 years to 11 years of age in two placebo-controlled 2-week seasonal allergic rhinitis trials. The safety of ALLEGRA at doses of 15mg and 30 mg given once and twice a day has been demonstrated in 969 pediatric subjects (6 months to 5 years of age) with allergic rhinitis in 3 pharmacokinetic studies and 3 safety studies. The safety of ALLEGRA for the treatment of chronic idiopathic urticaria in subjects 6 months to 11 years of age is based on cross-study comparison of the pharmacokinetics of ALLEGRA in adult and pediatric subjects and on the safety profile of fexofenadine in both adult and pediatric subjects at doses equal to or higher than the recommended dose.

The effectiveness of ALLEGRA for the treatment of seasonal allergic rhinitis in subjects 6 to 11 years of age was demonstrated in 1 trial (n=411) in which ALLEGRA tablets 30 mg twice daily significantly reduced total symptom scores compared to placebo, along with extrapolation of demonstrated efficacy in subjects aged 12 years and above, and the pharmacokinetic comparisons in adults and children. The effectiveness of fexofenadine hydrochloride 30 mg twice daily for the treatment of seasonal allergic rhinitis in patients 2 to 5 years of age is based on the pharmacokinetic comparisons in adult and pediatric subjects and an extrapolation of the demonstrated efficacy of fexofenadine hydrochloride in adult subjects with this condition and the likelihood that the disease course, pathophysiology, and the drug's effect are substantially similar in pediatric patients to those in adult patients. The effectiveness of ALLEGRA for the treatment of chronic idiopathic urticaria in patients 6 months to 11 years of age is based on the pharmacokinetic comparisons in adults and children and an extrapolation of the demonstrated efficacy of ALLEGRA in adults with this condition and the likelihood that the disease course, pathophysiology and the drug's effect are substantially similar in children to that of adult patients. 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.

The safety and effectiveness of ALLEGRA in pediatric patients under 6 months of age have not been established.

GERIATRIC USE

Clinical studies of ALLEGRA tablets and capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether this population responds differently from younger subjects. Other reported clinical experience has not identified differences in responses between the geriatric and younger subjects. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY).

ADVERSE REACTIONS

Seasonal Allergic Rhinitis

Adults

In placebo-controlled seasonal allergic rhinitis clinical trials in subjects 12 years of age and older, which included 2461 subjects receiving fexofenadine hydrochloride capsules at doses of 20 mg to 240 mg twice daily, adverse events were similar in fexofenadine hydrochloride- and placebo-treated subjects. All adverse events that were reported by greater than 1% of subjects who received the recommended daily dose of fexofenadine hydrochloride (60 mg capsules twice daily), and that were more common with fexofenadine hydrochloride than placebo, are listed in Table 1.

In a placebo-controlled clinical study in the United States, which included 570 subjects aged 12 years and older receiving fexofenadine hydrochloride tablets at doses of 120 or 180 mg once daily, adverse events were similar in fexofenadine hydrochloride- and placebo-treated subjects. Table 1 also lists adverse experiences that were reported by greater than 2% of subjects treated with fexofenadine hydrochloride tablets at doses of 180 mg once daily and that were more common with fexofenadine hydrochloride than placebo.

The incidence of adverse events, including drowsiness, was not dose-related and was similar across subgroups defined by age, gender, and race.

Table 1 Adverse experiences in subjects aged 12 years and older reported in placebo-controlled seasonal allergic rhinitis clinical trials in the United States
Twice-daily dosing with fexofenadine capsules at rates of greater than 1%
Adverse experience Fexofenadine 60 mg
Twice Daily
(n=679)
Placebo
Twice Daily
(n=671)
Viral Infection (cold, flu) 2.5% 1.5%
Nausea 1.6% 1.5%
Dysmenorrhea 1.5% 0.3%
Drowsiness 1.3% 0.9%
Dyspepsia 1.3% 0.6%
Fatigue 1.3% 0.9%
Once-daily dosing with fexofenadine hydrochloride tablets at rates of greater than 2%
Adverse experience Fexofenadine 180 mg
Once Daily
(n=283)
Placebo
(n=293)
Headache 10.6% 7.5%
Upper Respiratory Tract Infection 3.2% 3.1%
Back Pain 2.8% 1.4%

The frequency and magnitude of laboratory abnormalities were similar in fexofenadine hydrochloride- and placebo-treated subjects.

Pediatrics

Table 2 lists adverse experiences in subjects aged 6 years to 11 years of age which were reported by greater than 2% of subjects treated with fexofenadine hydrochloride tablets at a dose of 30 mg twice daily in placebo-controlled seasonal allergic rhinitis studies in the United States and Canada that were more common with fexofenadine hydrochloride than placebo.

Table 2 Adverse experiences reported in placebo-controlled seasonal allergic rhinitis studies in pediatric subjects aged 6 years to 11 years in the United States and Canada at rates of greater than 2%
Adverse experience Fexofenadine 30 mg
Twice Daily
(n=209)
Placebo
(n=229)
Headache 7.2% 6.6%
Accidental Injury 2.9% 1.3%
Coughing 3.8% 1.3%
Fever 2.4% 0.9%
Pain 2.4% 0.4%
Otitis Media 2.4% 0.0%
Upper Respiratory Tract Infection 4.3% 1.7%

Table 3 lists adverse events in subjects 6 months to 5 years of age in 3 open single- and multiple-dose pharmacokinetic studies and 3 placebo-controlled safety studies with fexofenadine hydrochloride capsule content (484 subjects) and suspension (50 subjects) at doses of 15 mg (108 subjects) and 30 mg (426 subjects) given twice a day.

Table 3 Adverse experiences reported in placebo-controlled studies in pediatric subjects with allergic rhinitis aged 6 months to 5 years of age at rates greater than 2%
Adverse experience Fexofenadine 15 mg
Twice Daily
Fexofenadine 30 mg
Twice Daily
Total Placebo
(n=108) (n=426) (n=534) (n=430)
Vomiting 12.0% 4.2% 5.8% 8.6%
Pyrexia 1.9% 4.5% 3.9% 7.0%
Cough 1.9% 4.0% 3.6% 3.3%
Otitis media 2.8% 3.8% 3.6% 3.3%
Diarrhoea 3.7% 2.8% 3.0% 2.6%
Rhinorrhoea 0.9% 2.1% 1.9% 0.9%
Upper respiratory tract infection 0.9% 2.1% 1.9% 4.0%
Somnolence 2.8% 0.7% 1.1% 0.2%

Chronic Idiopathic Urticaria

Adverse events reported by subjects 12 years of age and older in placebo-controlled chronic idiopathic urticaria studies were similar to those reported in placebo-controlled seasonal allergic rhinitis studies. In placebo-controlled chronic idiopathic urticaria clinical trials, which included 726 subjects 12 years of age and older receiving fexofenadine hydrochloride tablets at doses of 20 to 240 mg twice daily, adverse events were similar in fexofenadine hydrochloride- and placebo-treated patients. Table 4 lists adverse experiences in subjects aged 12 years and older which were reported by greater than 2% of subjects treated with fexofenadine hydrochloride 60 mg tablets twice daily in controlled clinical studies in the United States and Canada and that were more common with fexofenadine hydrochloride than placebo.

In a placebo-controlled clinical study in the United States, which included 167 subjects aged 12 years and older receiving fexofenadine hydrochloride 180 mg tablets, adverse events were similar in fexofenadine hydrochloride- and placebo-treated subjects. Table 4 also lists adverse experiences that were reported by greater than 2% of subjects treated with fexofenadine hydrochloride tablets at doses of 180 mg once daily and that were more common with fexofenadine hydrochloride than placebo.

The safety of fexofenadine hydrochloride in the treatment of chronic idiopathic urticaria in pediatric patients 6 months to 11 years of age is based on the safety profile of fexofenadine hydrochloride in adults and pediatric patients at doses equal to or higher than the recommended dose (see Pediatric Use).

Table 4 Adverse experiences reported in subjects 12 years of age and older in placebo-controlled chronic idiopathic urticaria studies
Twice-daily dosing with fexofenadine hydrochloride in studies in the United States and Canada at rates of greater than 2%
Adverse experience Fexofenadine 60 mg
Twice Daily
(n=191)
Placebo
(n=183)
Dyspepsia 4.7% 4.4%
Myalgia 2.6% 2.2%
Back Pain 2.1% 1.1%
Dizziness 2.1% 1.1%
Pain in extremity 2.1% 0.0%
Once-daily dosing with fexofenadine hydrochloride in a study in the United States at rates of greater than 2%
Adverse experience Fexofenadine 180 mg
Once Daily
(n=167)
Placebo
(n=92)
  
Headache 4.8% 3.3%
Nasopharyngitis 2.4% 2.2%
Upper respiratory tract infection 2.4% 2.2%

Events that have been reported during controlled clinical trials involving seasonal allergic rhinitis and chronic idiopathic urticaria subjects with incidences less than 1% and similar to placebo and have been rarely reported during postmarketing surveillance include: insomnia, nervousness, and sleep disorders or paroniria. In rare cases, rash, urticaria, pruritus and hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnea, flushing and systemic anaphylaxis have been reported.

OVERDOSAGE

Reports of fexofenadine hydrochloride overdose have been infrequent and contain limited information. However, dizziness, drowsiness, and dry mouth have been reported. Single doses of fexofenadine hydrochloride up to 800 mg (6 healthy subjects at this dose level), and doses up to 690 mg twice daily for 1 month (3 healthy subjects at this dose level) or 240 mg once daily for 1 year (234 healthy subjects at this dose level) were administered without the development of clinically significant adverse events as compared to placebo.

In the event of overdose, consider standard measures to remove any unabsorbed drug. Symptomatic and supportive treatment is recommended. Following administration of terfenadine, hemodialysis did not effectively remove fexofenadine, the major active metabolite of terfenadine, from blood (up to 1.7% removed).

No deaths occurred at oral doses of fexofenadine hydrochloride up to 5000 mg/kg in mice (110 times the maximum recommended daily oral dose in adults and children based on mg/m2) and up to 5000 mg/kg in rats (230 times the maximum recommended daily oral dose in adults and 210 times the maximum recommended daily oral dose in children based on mg/m2). Additionally, no clinical signs of toxicity or gross pathological findings were observed. In dogs, no evidence of toxicity was observed at oral doses up to 2000 mg/kg (300 times the maximum recommended daily oral dose in adults and 280 times the maximum recommended daily oral dose in children based on mg/m2).

DOSAGE AND ADMINISTRATION

ALLEGRA Tablets

Seasonal Allergic Rhinitis and Chronic Idiopathic Urticaria

Adults and Children 12 Years and Older

The recommended dose of ALLEGRA is 60 mg twice daily or 180 mg once daily with water. A dose of 60 mg once daily is recommended as the starting dose in patients with decreased renal function (see CLINICAL PHARMACOLOGY).

Children 6 to 11 Years

The recommended dose of ALLEGRA is 30 mg twice daily with water. A dose of 30 mg once daily is recommended as the starting dose in pediatric patients with decreased renal function (see CLINICAL PHARMACOLOGY).

ALLEGRA Oral Suspension

Seasonal Allergic Rhinitis

Children 2 to 11 Years

The recommended dose of ALLEGRA Oral Suspension is 30 mg twice daily. A dose of 30 mg (5 mL) once daily is recommended as the starting dose in pediatric patients with decreased renal function (see CLINICAL PHARMACOLOGY).

Chronic Idiopathic Urticaria

Children 6 Months to 11 Years

The recommended dose of ALLEGRA Oral Suspension is 30 mg (5 mL) twice daily for patients 2 to 11 years of age and 15 mg (2.5 mL) twice daily for patients 6 months to less than 2 years of age. For pediatric patients with decreased renal function, the recommended starting doses of ALLEGRA Oral Suspension are 30 mg (5 mL) once daily for patients 2 to 11 years of age and 15 mg (2.5 mL), once daily for patients 6 months to less than 2 years of age (see CLINICAL PHARMACOLOGY).

Shake bottle well, before each use.

HOW SUPPLIED

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 identifiers: 30 mg tablets have 03 on one side and a scripted E on the other; 60 mg tablets have 06 on one side and a scripted E on the other; and 180 mg tablets 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.

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.

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

©2006 sanofi-aventis U.S. LLC


Allegra (fexofenadine hydrochloride)
PRODUCT INFO
Product Code 0088-1106 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
fexofenadine hydrochloride (Fexofenadine) Active 30 MILLIGRAM  In 1 TABLET
croscarmellose sodium Inactive  
magnesium stearate Inactive  
microcrystalline cellulose Inactive  
sodium chloride Inactive  
cellulose acetate Inactive  
polyethylene glycol Inactive  
pregelatinized starch Inactive  
hypromellose Inactive  
iron oxide blends Inactive  
polyethylene glycol Inactive  
povidone Inactive  
silicone dioxide Inactive  
titanium dioxide Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color ORANGE (peach) Score 1
Shape ROUND Symbol false
Imprint Code 03;E Coating true
Size 6mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0088-1106-47 100 TABLET In 1 BOTTLE None
2 0088-1106-55 500 TABLET In 1 BOTTLE None

Allegra (fexofenadine hydrochloride)
PRODUCT INFO
Product Code 0088-1107 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
fexofenadine hydrochloride (Fexofenadine) Active 60 MILLIGRAM  In 1 TABLET
croscarmellose sodium Inactive  
magnesium stearate Inactive  
microcrystalline cellulose Inactive  
sodium chloride Inactive  
cellulose acetate Inactive  
polyethylene glycol Inactive  
pregelatinized starch Inactive  
hypromellose Inactive  
iron oxide blends Inactive  
polyethylene glycol Inactive  
povidone Inactive  
silicone dioxide Inactive  
titanium dioxide Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color ORANGE (peach) Score 1
Shape OVAL Symbol false
Imprint Code 06;E Coating true
Size 12mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0088-1107-47 100 TABLET In 1 BOTTLE None
2 0088-1107-55 500 TABLET In 1 BOTTLE None
3 0088-1107-49 100 TABLET In 1 BLISTER PACK None

Allegra (fexofenadine hydrochloride)
PRODUCT INFO
Product Code 0088-1109 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
fexofenadine hydrochloride (Fexofenadine) Active 180 MILLIGRAM  In 1 TABLET
croscarmellose sodium Inactive  
magnesium stearate Inactive  
microcrystalline cellulose Inactive  
sodium chloride Inactive  
cellulose acetate Inactive  
polyethylene glycol Inactive  
pregelatinized starch Inactive  
hypromellose Inactive  
iron oxide blends Inactive  
polyethylene glycol Inactive  
povidone Inactive  
silicone dioxide Inactive  
titanium dioxide Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color ORANGE (peach) Score 1
Shape OVAL Symbol false
Imprint Code 018;E Coating true
Size 17mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0088-1109-47 100 TABLET In 1 BOTTLE None
2 0088-1109-55 500 TABLET In 1 BOTTLE None

Allegra (fexofenadine hydrochloride)
PRODUCT INFO
Product Code 0088-1097 Dosage Form SUSPENSION
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
fexofenadine hydrochloride (Fexofenadine) Active 6 MILLIGRAM  In 1 MILLILITER
polypropylene glycol Inactive  
edetate disodium Inactive  
propylparaben Inactive  
butylparaben Inactive  
xanthan gum Inactive  
poloxamer 407 Inactive  
titanium dioxide Inactive  
sodium phosphate monobasic monohydrate Inactive  
sodium phosphate dibasic heptahydrate Inactive  
artificial raspberry cream flavor Inactive  
sucrose Inactive  
xylitol Inactive  
purified water Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 0088-1097-10 30 MILLILITER In 1 BOTTLE None
2 0088-1097-20 300 MILLILITER In 1 BOTTLE None

Revised: 10/2006