Fexofenadine Hydrochloride

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.

Uses

Fexofenadine Hydrochloride Tablets are indicated for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older. Symptoms treated effectively were sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes.

Fexofenadine Hydrochloride Tablets are indicated for treatment of uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older. It significantly reduces pruritus and the number of wheals.

Fexofenadine Hydrochloride Tablets are contraindicated in patients with known hypersensitivity to any of its ingredients.

Fexofenadine Hydrochloride Tablets 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 Fexofenadine Hydrochloride Tablets only as prescribed. Do not exceed the recommended dose. If any untoward effects occur while taking Fexofenadine Hydrochloride Tablets, discontinue use and consult the doctor.

The product should not be used by patients who are hypersensitive to it or to any of its ingredients.

Patients should be told that this product 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 tablet with water. Patients should also be advised to store the medication in a tightly closed container in a cool, dry place, away from children.

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.

The carcinogenic potential and reproductive toxicity of fexofenadine hydrochloride were assessed using terfenadine studies with adequate fexofenadine hydrochloride 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 from the maximum recommended human 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 dietary 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 hydrochloride exposures that were approximately 3 times the exposure of the maximum recommended human daily oral dose of 180 mg fexofenadine hydrochloride). In mice, fexofenadine hydrochloride produced no effect on male or female fertility at average dietary doses up to 4438 mg/kg (approximately 10 times the maximum recommended human daily oral dose of fexofenadine hydrochloride 180 mg based on comparison of AUCs).

PREGNANCY

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 3 and 30 times, respectively, the exposure from the maximum recommended human daily oral dose of fexofenadine hydrochloride of 180 mg based on comparison of AUCs).

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

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

Dose-related decreases in pup weight gain and survival were observed in rats exposed to an oral dose of 150 mg/kg of terfenadine (approximately 3 times the maximum recommended human daily oral dose of fexofenadine hydrochloride of 180 mg in adults based on comparison of fexofenadine hydrochloride AUCs).

The recommended dose in patients 6 to 11 years of age is based on cross-study comparison of the pharmacokinetics of fexofenadine hydrochloride 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 fexofenadine hydrochloride tablets at a dose of 30 mg twice daily has been demonstrated in 438 pediatric subjects 6 to 11 years of age in two placebo-controlled 2-week seasonal allergic rhinitis trials. The safety of fexofenadine hydrochloride for the treatment of chronic idiopathic urticaria in subjects 6 to 11 years of age is based on cross-study comparison of the pharmacokinetics of fexofenadine hydrochloride 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 fexofenadine hydrochloride for the treatment of seasonal allergic rhinitis in subjects 6 to 11 years of age was demonstrated in 1 trial (n=411) in which fexofenadine hydrochloride 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 for the treatment of chronic idiopathic urticaria in patients 6 to 11 years of age is based on an extrapolation of the demonstrated efficacy of fexofenadine hydrochloride 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.

Three clinical safety studies comparing 15 mg twice daily (n=85) and 30 mg twice daily (n=330) of an experimental formulation of fexofenadine to placebo (n=430) have been conducted in pediatric subjects aged 6 months to 5 years. In general, fexofenadine hydrochloride was well tolerated in these studies. No unexpected adverse events were seen given the known safety profile of fexofenadine and likely adverse reactions for this patient population. (See ADVERSE REACTIONS and CLINICAL PHARMACOLOGY.)

The safety and effectiveness of fexofenadine hydrochloride in pediatric patients under 6 years of age have not been established.

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.

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

Table 2 lists adverse experiences in subjects aged 6 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.

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

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.

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 volunteers at this dose level), and doses up to 690 mg twice daily for 1 month (3 healthy volunteers at this dose level) or 240 mg once daily for 1 year (234 healthy volunteers 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 human daily oral dose in adults and 200 times the maximum recommended human daily oral dose in children based on mg/m²) and up to 5000 mg/kg in rats (230 times the maximum recommended human daily oral dose in adults and 400 times the maximum recommended human 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 human daily oral dose in adults and 530 times the maximum recommended human daily oral dose in children based on mg/m²).

The recommended dose of Fexofenadine Hydrochloride Tablets 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).

The recommended dose of Fexofenadine Hydrochloride Tablets 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).

The recommended dose of Fexofenadine Hydrochloride Tablets 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).

The recommended dose of Fexofenadine Hydrochloride Tablets 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).

Fexofenadine Hydrochloride Tablets 60 mg are available in HDPE bottles of 100 (NDC 66993-107-02) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal and HDPE bottles of 500 (NDC 66993-104-04) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal.

Fexofenadine Hydrochloride Tablets 180 mg are available in HDPE bottles of 100 (NDC 66993-109-02) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal and HDPE bottles of 500 (NDC 66993-109-04) with a polypropylene screw cap containing a pulp/wax liner with heat-sealed foil inner seal.

Fexofenadine Hydrochloride Tablets are coated with a peach colored film coating. Tablets have the following unique identifiers: 30 mg tablets have 03 on one side, 60 mg tablets have 06 on one side, and 180 mg tablets have 018 on one side.

Store Fexofenadine Hydrochloride Tablets at controlled room temperature 20–25°C (68–77°F). (See USP Controlled Room Temperature). Fexofenadine Hydrochloride Tablets should be protected from excessive moisture.

Rev. August 2006
Manufactured by:
sanofi-aventis U.S. LLC.
Bridgewater, NJ 08807  USA

Manufactured for:
Prasco Laboratories
Cincinnati, OH 45249  USA

©2006 sanofi-aventis U.S. LLC.

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