Fexofenadine Hydrochloride   Tablets  

JANUARY 2005

1007210103

Rx only

Fexofenadine hydrochloride 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:

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.

Fexofenadine hydrochloride tablets for oral administration contains 30, 60, or 180 mg fexofenadine hydrochloride (depending on the dosage strength). The inactive ingredients are as follows: calcium stearate, colloidal silicon dioxide, crospovidone, FD&C red no. 40, FD&C yellow no. 6, hypromellose, polyethylene glycol, polysorbate 80, povidone, powdered cellulose, and titanium dioxide.

Fexofenadine hydrochloride is an antihistamine with selective peripheral H₁-receptor antagonist activity. Both enantiomers of fexofenadine hydrochloride displayed approximately equipotent antihistaminic effects. Fexofenadine inhibited histamine release from peritoneal mast cells in rats. In laboratory animals, no anticholinergic, alpha₁-adrenergic or beta-adrenergic-receptor blocking effects were observed. 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.

Special population pharmacokinetics (for geriatric subjects, renal and hepatic impairment), obtained after a single dose of 80 mg fexofenadine hydrochloride, were compared to those for normal subjects from a separate study of similar design. While subject weights were relatively uniform between studies, these adult special population patients were substantially older than the healthy, young volunteers. Thus, an age effect may be confounding the pharmacokinetic differences observed in some of the special populations.

Fexofenadine hydrochloride is 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 is 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 is contraindicated in patients with known hypersensitivity to any of its ingredients.

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

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. In vivo animal studies also suggest that in addition to increasing absorption, ketoconazole decreases fexofenadine hydrochloride gastrointestinal secretion, while erythromycin may also decrease biliary excretion.

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

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 respectively approximately 3 and 5 times the exposure from the maximum recommended daily oral dose of fexofenadine hydrochloride in adults and children).

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 hydrochloride exposures that were approximately 3 times the exposure of the maximum recommended daily oral dose of fexofenadine hydrochloride in adults).

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 fexofenadine hydrochloride is administered to a nursing woman.

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

The effectiveness of fexofenadine hydrochloride for the treatment of seasonal allergic rhinitis in patients 6 to 11 years of age was demonstrated in one 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 patients ages 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.

Additional clinical study information related to safety of fexofenadine in pediatric patients is approved for Aventis Pharmaceuticals’ fexofenadine hydrochloride drug products. However, due to Aventis Pharmaceuticals’ marketing exclusivity rights, this drug product in not labeled for use in children less than 6 years of age.

Clinical studies of fexofenadine hydrochloride tablets did not include sufficient numbers of subjects aged 65 years and over to determine whether this population responds differently from younger patients. Other reported clinical experience has not identified differences in responses between the geriatric and younger patients. 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 may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY).

Adverse events reported by patients 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 patients 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 3 uls adverse experiences in patients aged 12 years and older which were reported by greater than 2% of patients 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. 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 patients with incidences less than 1% and similar to placebo and have been rarely reported during postmarketing surveillance include: insomnia, nervousness, and sleep disorders or paranoia. In rare cases, rash, urticaria, pruritis, and hypersensitivty 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 (six normal volunteers at this dose level), and doses up to 690 mg twice daily for 1 month (three normal volunteers at this dose level) or 240 mg once daily for 1 year (234 normal 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.

Hemodialysis did not effectively remove fexofenadine hydrochloride from blood (1.7% removed) following terfenadine administration.

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 200 times the maximum recommended daily oral dose in children based on mg/m²) and up to 5000 mg/kg in rats (230 times the maximum recommended daily oral dose in adults and 400 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 530 times the maximum recommended daily oral dose in children based on mg/m²).

Fexofenadine Hydrochloride Tablets are available as:

30 mg: Pink, round, film-coated, biconvex, unscored tablet. Debossed with stylized b over 30 on one side and 721 on the other side.

Available in bottles of:

60 mg: Pink, round, film-coated, biconvex, unscored tablet. Debossed with stylized b over 60 on one side and 722 on the other side.

Available in bottles of:

180 mg: Pink, capsule-shaped, film-coated, biconvex, unscored tablet. Debossed with stylized b 180 on one side and 723 on the other side.

Available in bottles of:

Dispense with a child-resistant closure in a tight, light-resistant container.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from excessive moisture.

MANUFACTURED BY
BARR LABORATORIES, INC.
POMONA, NY 10970

JANUARY 2005
BR-721,722,723