Xadine™

[Fexofenadine]

Description / Properties

Mechanism of Action

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. Radio labeled tissue distribution studies in rats indicated that fexofenadine does not cross the blood – brain barrier.

Clinical Pharmacokinetics

Absorption: Fexofenadine hydrochloride was rapidly absorbed following oral administration of a single dose of two 60mg capsules to healthy male volunteers with a mean time to maximum plasma concentration occurring at 2.6 hours post – dose. After administration of a single 60mg capsule to healthy subjects, the mean maximum plasma concentration was 131ng/mL. Following single dose oral administrations of either the 60 and 180 mg tablet to healthy, adult male volunteers, mean maximum plasma concentrations 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 240mg (120 twice daily).

Distribution: Fexofenadine hydrochloride is 60% to 70% bound to plasma proteins primarily albumin and a1-acid glycoprotein.

Elimination: The mean elimination half-life of fexofenadine was 14.4 hours following administration of 60mg, twice daily, in normal volunteers. 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 unabsorbed drug or the result of biliary excretion.

Metabolism: Approximately 5% of the total oral dose was metabolized.

Special Populations: Special population pharmacokinetics (for geriatric subjects renal and hepatic impairment), obtained after a single dose of 80mg fexofenadine hydrochloride, were compared to those for normal subjects from a separate study of similar design. While subject weights ere 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.

Seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria (Ciu) patients. The pharmacokinetics of fexofenadine hydrochloride in seasonal allergic rhinitis and chronic idiopathic urticaria patients were similar to those in healthy subjects.

Geriatric Subjects: In older subjects (> 65 years old), peak plasma levels of fexofenadine were 99% greater than those observed in normal volunteers (<65 years old). Mean elimination half-lives were similar to those observed in normal volunteers. Pediatric Patients: Cross study comparisons indicated that fexofenadine hydrochloride area under the curve (AUC) following oral administration of a 60 mg dose to 7-12 years old pediatric allergic rhinitis patients was 56% greater compared to healthy adult subjects given the same dose. Plasma exposure in pediatricd patients given 30mg fexofenadine hydrochloride is comparable to adults given 60mg.

Renal Impairment In patients with mild to moderate (creatinine clearance 41-80 mL/min) and severe (Creatinine clearance 11-40 mL / min) renal impairment, peak plasma levels of fexofenadine were 87% and 111% greater, respectively and mean elimination half-lives were 59%and 72% longer, respectively, than observed in normal volunteers. Peak plasma levels in patients on dialysis (creatinine clearance < 10mL/min) were 82% greater and half-life was 31% longer than observed in normal volunteers. Based on increases in bioavailability and half-life, a dose of 60mg once daily is recommended as the starting dose in patients with decreased renal function.

Hepatic Impairment. The pharmacokinetics of fexofenadien hydrochloride in patients with hepatic disease did not differ substantially from that observed in healthy patients.

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 40mg fexofenadine hydrochloride demonstrated that the drug exhibitis 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. Histamine skin wheal and flare studies in 7 to 12 years old patients showed that following a single dose of 30 or 60mg, antihistamine effect was observed at 1 hour and reached a maximum by 4 hours. Greater than 49% inhibition of wheal area and 74% inhibition of flare area were maintained for 8 hours following the 30 and 60mg dose. Effects on QTc. In dogs (30mg/kg/orally twice a day), and in fexofenadinehydrochloride QTc. In dogs the plasma fexofenadine concentration was approximately 9 times the therapeutic plasma concentrations in adults receiving the maximum recommended daily oral dose. In rabbits, the plasma fexofenadine concentration was approximately 20times the therapeutic plasma concentration in adults receiving the maximum recommended daily oral dose. No effect was observed on calcium channel current, delayed potassium channel current, or action potential duration in guinea pig myocytes, sodium current in rat neonatal myocytes, or on several delayed rectifier potassium channels cloned from human heart at concentrations up to 1 X 10-5 M of fexofenadine hydrochloride. No statistically significant increase in mean QTc interval compared to placebo was observed in 714 seasonal allergic in doses of 60 to 240 mg twice daily for two weeks. Pediatric patients from two placebo controlled trials (n=855) treated with up to 60mg fexofenadine hydrochloride twice daily demonstrated no significant treatment or dose-related increases in QTc. In addition, non statistically significant increase in mean TQc interval compared to placebo was observed in 40 healthy volunteers given fexofenadine hydrochloride as an oral solution at doses up to 400 mg twice daily for 6 days, or in 231 healthy volunteers given fexofenadine hydrochloride 240mg once daily for 1 year.

Metabolism: Approximately 5% of the total oral dose was metabolized.

Geriatric Use: Clinical studies of Xadine™tablets and capsules 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 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.

Indications

Seasonal Allergic Rhinitis Xadine™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).

Chronic Idiopathic Urticaria

Xadine™is indicated for treatment of uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6years of age and older. It significantly reduces pruritus and the number of wheals.

Contraindication

Xadine™is contraindicated in patients with known hypersensitivity to any of its ingredients.

Drug Interactions

Drug Interaction with Erythromycin and Ketoconazole Fexofenadine hydrochloride has been shown 6 exhibit minimal (ca. 5%) metabolism. However, con-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 ketocomazole. In two separate studies, fexofenadine hydrochloride 120mg twice daily (two times the recommended twice daily dose) was co administered with erythromycin 500mg every 8 hours or ketoconazole 400mg once daily under steady – state conditions to normal, healthy volunteers (n=24, each study). No. differences in adverse events or QTc 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: [See table below] The changes in plasma levels were within the range of plasma levels 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 fexofinadine gastrointestinal absorption. In vivo animal studies also suggest that in addition to increasing absorptionl ketoconazole decreases fexofenadine hydrochlrodie gastrointestinal secretion, while erythromycin may also decrease biliary excretion.

Drug Interactions with Antacid Administration of 120mg of fexofenadine hydrochloride (2 X 60 mg capsule) within 15 minutes of an aluminium and magnesium containing antacid (Maalox R decreased fexofenadine AUC by 41% and C max by 43%.Xadine™should not be taken closely in time with aluminium and magnesium containing antacids.

Carcinogenesis, Mutagenesis, Impairment of Fertility 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-concentrations vs. Time [AUC] values. No. evidence of carcinogenicity was observed in an 18-month study in mice an din a 24-month study in rats at oral doses up to 150mg/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 For ward Mutation, and Rat Lymphocyte Chromosomal Alberrassay) tests, fexofenadine hydrochloride revealed no evidence of mutagenicity. In rat fertility studies, dose-related reductions in implants and increases in post implantation losses were observed at fexofenadine hydrochloride ere approximately 3 times the exposure of the maximum recommended daily oral dose of fexofenadine hydrochloride in adults).

Side Effects

Seasonal Allergic Rhinitis Adults. In placebo-controlled seasonal allergic rhinitis clinical trials in patients 12 years of age and older, which included 2461 patients receiving fexofenadine hydrochloride capsules at doses of 20 mg to 240 mg twice daily, adverse events were similar in fexofenadine hydrochloride and (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 patients aged 12 years and older receiving fexofenadien hydrochloride tablets at doses of 120 or 180 mg once daily, adverse events were similar in fexofenadine hydrochloride and placebo-treated patients. Table # 1 also lists adverse experiences that were reported by greater than 2% of patients 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 patients.

Warning and Precautions

Nursing Mothers. 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.

Pediatric Use. The recommended dose in patients 6 to 11 years of age is based on cross-study comparison of the pharmacokinetics of Xadine™in adults and pediatric patients and on the safety profile of fexofenadien hydrochloride in both adult and pediatric patients at doses equal to or higher than the recommended doses. The safety of Xadine™ tablets at a dose of 30mg twice daily has been demonstrated in 438 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 Xadine™ tablets at a dose of 30mg 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 Xadine™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 Xadine™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 Xadine™for the treatment of seasonal allergic rhinitis in patients 6 to 11 years of age was demonstrated in one trial (n=411) in which Xadine™tablets 30mg 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 Xadine™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 Xadine™in adults with the condition and the likelihood that the disease course, pathophysiology and the drug’s effect are substantially similar in children to that of adult patients. The safety and effectiveness of Xadine™in pediatric patients under 5 years of age have not been established.

Dosage

Seasonal Allergic Rhinitis Adults and Children 12 Years and Older. The recommended dose of Xadine™ is 60 mg twice daily or 180mg once daily. A dose of 60 mg once daily is recommended as the starting dose in patients with decreased renal function.

Chronic Idiopathic Urticaria Adults and Children 12 Years and Older. The recommended dose of Xadine™ is 60mg twice daily. A dose of 60 mg once daily is recommended as the starting dose in patients with decreased renal function.

Children 6 to 11 Years. The recommended dose of Xadine™ is 30mg twice daily. A dose of 30mg once daily is recommended as the starting dose in pediatric patients with increased renal function

Presentations Available

Xadine™, purple coloured Tablets , with SEARLE engraved on one side and scored on other are available in a blister packs of 10`s (10`s X 1 Strip).

Xadine™ 60mg Tablets: Packet contains one strip of 10 tablets. Each film coated tablet contains 60mg Fexofenadine Hydrochloride as active ingredient.

Xadine™ 120mg Tablets: Packet contains one strip of 10 tablets. Each film coated tablet contains 120mg Fexofenadine Hydrochloride as active ingredient.

Xadine™ 180mg Tablets: Packet contains one strip of 10 tablets. Each film coated tablet contains 180mg Fexofenadine Hydrochloride as active ingredient.

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