Pharmacology: Pharmacodynamics: Tablet: Wheal and Flare: Human histamine skin wheal and flare studies conducted in adults following single- and twice-daily doses of fexofenadine HCl 20 and 40 mg demonstrated that the drug exhibits an antihistamine effect by 1 hr, achieves maximum effect at 2-3 hrs and their effect is still seen at 12 hrs. There was no evidence of tolerance to these effects after 28 days of dosing. The clinical significance of these observations is not known.
In children (6-11 years), fexofenadine HCl suppressed histamine-induced wheal and flare to a similar extent to that observed in adults. Histamine skin wheal and flare studies in pediatric patients showed that following a single dose of 30 or 60 mg, antihistamine effect was observed at 1 hr and reached a maximum by 3 hrs. Greater than 49% inhibition of wheal area and 74% inhibition of flare area were maintained for 8 hrs following the 30- and 60-mg dose.
Effects on QTc: In dogs (10 mg/kg/day, orally for 5 days) and rabbits (10 mg/kg IV over 1 hr), fexofenadine did not prolong QTc at plasma concentrations that were at least 28 and 63 times, respectively, the therapeutic plasma concentrations in man (based on a 60-mg twice-daily fexofenadine HCl dose). No effect was observed on calcium channel current, delayed K+ channel current or action potential duration in guinea pig myocytes, Na+ current in rat neonatal myocytes, or on the delayed rectifier K+ channel cloned from human heart at concentrations up to 1 x 10-5 M of fexofenadine. This concentration was at least 32 times the therapeutic plasma concentration in man (based on a 60-mg twice-daily fexofenadine HCl dose).
No statistically significant increase in mean QTc interval compared to placebo was observed in 714 seasonal allergic rhinitis patients given fexofenadine HCl capsules in doses of 60-240 mg twice daily for 2 weeks or in 40 healthy volunteers given fexofenadine HCl as an oral solution at doses up to 400 mg twice daily for 6 days. Pediatric patients from 2 placebo controlled trials (n=855) treated with up to 60 mg fexofenadine HCl twice daily demonstrated no significant treatment or dose-related increases in QTc.
A 1 year study designed to evaluate safety and tolerability of 240 mg of fexofenadine HCl (n=240) compared to placebo (n=237) in healthy subjects, did not reveal a statistically significant increase in the mean QTc interval for the fexofenadine HCl treated group when evaluated pretreatment and after 1, 2, 3, 6, 9 and 12 months of treatment.
Mechanism of Action: Fexofenadine HCl, the major active metabolite of terfenadine, is an antihistamine with selective peripheral H1-receptor antagonist activity. It inhibited antigen-induced bronchospasm in sensitized guinea pigs and histamine release from peritoneal mast cells in rats. In laboratory animals, no anticholinergic or α1-adrenergic receptor-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.
Oral suspension: Fexofenadine hydrochloride is an anti-histaminic with peripheral H1-receptors selective antagonistic activity. Fexofenadine inhibited antigen-induced bronchospasm in sensitized guinea pigs and the release of histamine from the peritoneal mast cells in rats. In laboratory animals, no anticholinergic effects or blockage of alpha1-adrenergic receptors were observed. In addition, no sedative or other effects on the central nervous system were observed. Tissue distribution studies conducted with radio-labeled fexofenadine hydrochloride in rats demonstrated that fexofenadine does not cross the hematoencephalic barrier.
Pharmacokinetics: Tablet: Absorption: Fexofenadine HCl was rapidly absorbed following oral administration of a single dose of two 60-mg cap to healthy male volunteers with a mean time to maximum plasma concentration occurring at 2.6 hrs post-dose. After administration of a single 60-mg dose as an oral solution to healthy subjects, the mean plasma concentration was 209 ng/mL. Mean steady-state peak plasma concentrations of 286 ng/mL were observed when healthy volunteers were administered with multiple doses of fexofenadine HCl (60 mg oral solution every 12 hrs for 10 doses). Although the absolute bioavailability of fexofenadine HCl capsules is unknown, the capsules are bioequivalent to an oral solution. In addition, tablets are also bioequivalent to capsules. Fexofenadine HCl pharmacokinetics were linear for oral doses up to a total daily dose of 240 mg (120 mg twice daily).
Distribution: Fexofenadine is 60-70% bound to plasma proteins, primarily albumin and α1-acid glycoprotein.
Elimination: The mean elimination half-life of fexofenadine was 14.4 hrs following administration of 60 mg, twice daily in normal volunteers.
Human mass balance studies documented a recovery of approximately 80% and 11% of the [14C] fexofenadine HCl dose in the feces and urine, respectively. Because the absolute bioavailability of fexofenadine HCl has not been established, it is unknown if the fecal component represents unabsorbed drug or the result of biliary excretion.
Fexofenadine clearance in children (6-11 years) is approximately 40% slower than in adults. Therefore, a dose of 30 mg twice daily was determined to provide plasma levels (AUC and Cmax) in children which were comparable to plasma levels achieved in adults following 120 mg once daily.
Metabolism: Approximately 5% of the total dose was metabolized.
The pharmacokinetics of fexofenadine HCl in seasonal allergic rhinitis and chronic idiopathic urticaria patients were similar to those in healthy subjects. Peak fexofenadine plasma concentrations were similar between adolescent (12-16 years) and adult patients.
Special Populations: Special population pharmacokinetics (for geriatric subjects, renal and hepatic impairment), obtained after a single dose of fexofenadine HCl 80 mg, 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.
Geriatric Subjects: In older subjects (≥65 years), peak plasma levels of fexofenadine were 99% greater than those observed in normal volunteers (<65 years). Mean elimination half-lives were similar to those observed in normal volunteers.
Pediatrics Patients: Cross study comparisons indicated that fexofenadine HCl area under the curve (AUC) following oral administration of a 60-mg dose to 7- to 12-year old pediatric allergic rhinitis patients was 56% greater compared to healthy adult subjects given the same dose. Plasma exposure in pediatric patients given fexofenadine HCl 30 mg is comparable to adults given 60 mg.
Renal Impairment: In patients with mild to moderate (Clcr 41-80 mL/min) and severe (Clcr 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 (Clcr ≤10 mL/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 60 mg once daily is recommended as the starting dose in patients with decreased renal function. (See Dosage & Administration.)
Hepatic Impairment: The pharmacokinetics of fexofenadine HCl in patients with hepatic disease did not differ substantially from that observed in healthy subjects.
Effect of Gender: Across several trials, no clinically significant gender-related differences were observed in the pharmacokinetics of fexofenadine HCl.
Oral suspension: Fexofenadine hydrochloride is rapidly absorbed after oral administration, with its Tmax occurring within approximately 1-3 hours from dose administration. The mean Cmax value was approximately 142 ng/mL after the administration of a single dose of 60 mg, approximately 289 ng/mL after a single dose of 120 mg and approximately 494 ng/mL after a 180 mg-single dose.
Plasma exposures resulting from single doses of 15, 30 and 60 mg in children from 2-11 years of age are dose-proportional and can be compared to those produced by the corresponding single doses of 30 mg, 60 mg and 120 mg in adults, respectively. The dose of 30 mg, twice a day, was determined to provide plasma levels area under the curve (AUC) in pediatric patients, which are comparable to those reached in adults after a dose of 120 mg. A 5 mL oral dose of the suspension containing fexofenadine hydrochloride 30 mg is bioequivalent to a dose of 30 mg of fexofenadine hydrochloride tablets. After a single 30 mg dose of TELFAST (ORAL SUSPENSION) was administered to healthy adults, the average Cmax was 118 ng/mL and occurred within 1 hour. The administration of 30 mg of TELFAST (ORAL SUSPENSION) with a meal rich in fat reduced the AUC and mean Cmax approximately 30 and 47%, respectively, in healthy adults.
Fexofenadine binds to the plasma proteins at a rate of approximately 60-70%. Insignificant amounts of fexofenadine are metabolized. After the administration of a 60 mg single dose of fexofenadine hydrochloride, 80% of the total dose was recovered in the feces and 11% in the urine. After multiple doses, the average elimination half-life of fexofenadine was 11-16 hours. The main route of elimination is believed to be through biliary excretion, whereas up to 10% of the dose taken is excreted unchanged in the urine.
The pharmacokinetics of fexofenadine hydrochloride, in single and multiple doses, is linear within a dose from 20 mg and a dose of 120 mg. One dose of 240 mg, twice a day, caused a slightly greater than proportional increase (8.8%) in the area under the curve, at steady state.
Toxicology: Pre-clinical safety data: Oral suspension: The carcinogenic potential of fexofenadine hydrochloride was assessed through studies with terfenadine and supporting pharmacokinetic studies which demonstrated the proper exposure to fexofenadine hydrochloride (through the area under the curve concentration plasma values - AUC). No evidence of carcinogenicity was observed in rats and mice with terfenadine (up to 150 mg/kg/day), resulting in a plasma exposure to fexofenadine of up to 4 times the therapeutic value in humans (based on 60 mg fexofenadine hydrochloride, twice a day).
Several in vitro and in vivo studies conducted with fexofenadine hydrochloride did not demonstrate mutagenicity. When fexofenadine hydrochloride was administered as 2000 mg/kg oral doses in acute toxicity studies conducted with several animal species, no clinical signs of toxicity and no effect on body weight or food intake were observed. No relevant treatment-related effects were observed in rodents after necropsy. Dogs tolerated 450 mg/kg, administered twice a day, for 6 months and did not exhibit any toxicity other than occasional vomit.
Clinical Studies: Tablet: Adults: In three 2-week multicenter, randomized, double-blind, placebo-controlled trials in patients 12-68 years with seasonal allergic rhinitis (n=1634), fexofenadine HCl 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-hr interval. In these studies, there was no additional reduction in total symptom scores with higher doses of fexofenadine HCl up to 240 mg twice daily. Although the number of subjects in some of the subgroups was small, there were no significant differences in the effect of fexofenadine HCl across subgroups of patients defined by gender, age and race. Onset of action for reduction in total symptom scores, excluding nasal congestion, was observed at 60 min compared to placebo following a single 60-mg fexofenadine HCl dose administered to patients with seasonal allergic rhinitis who were exposed to ragweed pollen in an environmental exposure unit.
Pediatrics: Two 2-week multicenter, randomized, placebo-controlled, double-blind trials in 877 pediatric patients (6-11 years) 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 patients, all 3 doses of fexofenadine HCl 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. Furthermore, exposure in pediatric patients given fexofenadine HCl 30 mg is comparable to adults given 60 mg.
Oral suspension: Efficacy results: Fexofenadine hydrochloride inhibited the formation of papule and erythema caused by histamine. After single dose and 2x/day oral doses of fexofenadine hydrochloride it was demonstrated that the drug exhibits an anti-histaminic effect, starting within one hour and achieving maximum effect within 2 to 3 hours, and the effect is still observed at least 12 hours. More than 80% maximum inhibition was achieved in the areas of formation of the papule and erythema. No tolerance to these effects was observed after 28 days. Clinical studies conducted on allergic rhinitis demonstrated that one 120 mg dose is sufficient for 24 hours efficacy, using total symptom score assessment as the primary end-point. In children from 6 to 11 years of age, the suppressive effect of fexofenadine hydrochloride on the histamine-induced papule and erythema were comparable to those in adults with similar exposure.
In the integrated analysis of a phase III double-blind placebo-controlled study involving 1369 children from 6 to 11 years of age with allergic rhinitis, the 30 mg-fexofenadine hydrochloride twice a day was significantly better than placebo in reducing the total symptom score (p = 0.0001). All individual symptoms components including rhinorrhea, sneezing, cough, itchy/red/watery eyes, itchy nose/palate/throat and nasal congestion showed significant improvement (p = 0.0334 to p = 0.0001) with fexofenadine hydrochloride.
The effectiveness of fexofenadine hydrochloride 30 mg twice a day in the treatment of seasonal allergic rhinitis in patients from 2 to 5 years of age is based on pharmacokinetic comparisons in adult and pediatric subjects and an extrapolation which demonstrated the efficacy of fexofenadine hydrochloride in adult and older pediatric individuals in these conditions and the progress of the disease, the physiopathology, and the effects of the drug are substantially similar in pediatric and adult subjects. The effectiveness of TELFAST (ORAL SUSPENSION) in treating chronic idiopathic urticaria in patients from 6 months to 11 years of age is based on pharmacokinetic comparisons of adults and children and an extrapolation of demonstrated efficacy of TELFAST (ORAL SUSPENSION) in adults in these conditions and the progress of this disease, the physiopathology and the effects of the drug are substantially similar in pediatric and adult patients. The administration of a 15 mg dose of fexofenadine hydrochloride to pediatrics individuals from 6 months to less than 2 years of age and a 30 mg dose for pediatric individuals from 2 to 11 years of age resulted in an exposure comparable to that of adults receiving a 60 mg dose.
The onset of reduction in total symptom scores was observed at 60 minutes as compared to placebo following a 60 mg single dose of fexofenadine hydrochloride administered to subjects with seasonal rhinitis who were exposed to ragweed pollen in an environmental exposure unit.
In patients with allergic rhinitis who received doses of up to 240 mg of fexofenadine hydrochloride, twice a day, for 2 weeks, no significant differences in QTc were observed when compared to placebo. Likewise, no alterations in the QTc interval were observed in healthy patients after the intake of up to 400 mg of fexofenadine hydrochloride, twice a day, for 6.5 days and 240 mg, once a day for 1 year, when compared to placebo. In children from 6 to 11 years of age, no significant differences in QTc were observed after the administration of up to 60 mg of fexofenadine hydrochloride, twice a day, for 2 weeks when compared to placebo. Fexofenadine, at concentrations 32 times higher than the therapeutic concentration in men, did not have any effect on the delayed rectifier K+ channel cloned from human heart.