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Pharmacotherapeutic group: Antihistamines for systemic use. ATC code: R06A X26.
Film-coated tablet: Pharmacology: Pharmacodynamics: Mechanism of action: Fexofenadine hydrochloride is a non-sedating H1 antihistamine. Fexofenadine is a pharmacologically active metabolite of terfenadine.
Clinical efficacy and safety: Human histamine wheal and flare studies following single and twice daily doses of fexofenadine hydrochloride demonstrate that the medicinal product exhibits an antihistaminic effect beginning within one hour, achieving maximum at 6 hours and lasting 24 hours. There was no evidence of tolerance to these effects after 28 days of dosing. A positive dose-response relationship between doses of 10 mg to 130 mg taken orally was found to exist. In this model of antihistaminic activity, it was found that doses of at least 130 mg were required to achieve a consistent effect that was maintained over a 24-hour period. Maximum inhibition in skin wheal and flare areas were greater than 80%. Clinical studies conducted in seasonal allergic rhinitis have shown that a dose of 120 mg is sufficient for 24-hour efficacy.
No significant differences in QTc intervals were observed in seasonal allergic rhinitis patients given fexofenadine hydrochloride up to 240 mg twice daily for 2 weeks when compared to placebo. Also, no significant change in QTc intervals was observed in healthy subjects given fexofenadine hydrochloride up to 60 mg twice daily for 6 months, 400 mg twice daily for 6.5 days and 240 mg once daily for 1 year, when compared to placebo. Fexofenadine at concentrations 32 times greater than the therapeutic concentration in man had no effect on the delayed rectifier K+ channel cloned from human heart.
Fexofenadine hydrochloride (5-10 mg/kg po) inhibited antigen-induced bronchospasm in sensitised guinea pigs and inhibited histamine release at supratherapeutic concentrations (10-100 μM) from peritoneal mast cells.
Pharmacokinetics: Absorption: Fexofenadine hydrochloride is rapidly absorbed into the body following oral administration, with Tmax occurring at approximately 1-3 hours post-dose. The mean Cmax value was approximately 427 ng/ml and 494 ng/ml following the administration of a 120 mg dose once daily and a 180 mg dose once daily, respectively.
Distribution: Fexofenadine is 60-70% plasma protein bound.
Biotransformation and elimination: Fexofenadine undergoes negligible metabolism (hepatic or non-hepatic), as it was the only major compound identified in urine and faeces of animals and man. The plasma concentration profiles of fexofenadine follow a bi-exponential decline with a terminal elimination half-life ranging from 11 to 15 hours after multiple dosing. The single and multiple dose pharmacokinetics of fexofenadine are linear for oral doses up to 120 mg BID. A dose of 240 mg BID produced slightly greater than proportional increase (8.8%) in steady-state area under the curve, indicating that fexofenadine pharmacokinetics are practically linear at these doses between 40 mg and 240 mg taken daily. The major route of elimination is believed to be via biliary excretion while up to 10% of ingested dose is excreted unchanged through the urine.
Toxicology: Preclinical safety data: Dogs tolerated 450 mg/kg administered twice daily for 6 months and showed no toxicity other than occasional emesis. Also, in single dose dog and rodent studies, no treatment-related gross findings were observed following necropsy.
Radiolabelled fexofenadine hydrochloride in tissue distribution studies of the rat indicated that fexofenadine did not cross the blood-brain barrier.
Fexofenadine hydrochloride was found to be non-mutagenic in various in vitro and in vivo mutagenicity tests.
The carcinogenic potential of fexofenadine hydrochloride was assessed using terfenadine studies with supporting pharmacokinetic studies showing fexofenadine hydrochloride exposure (via plasma AUC values). No evidence of carcinogenicity was observed in rats and mice given terfenadine (up to 150 mg/kg/day).
In a reproductive toxicity study in mice, fexofenadine hydrochloride did not impair fertility, was not teratogenic, and did not impair pre- or postnatal development.
Oral suspension: Pharmacology: The antihistaminic effects of fexofenadine have been demonstrated in animal systems in vitro and in vivo. Oral administration of fexofenadine to guinea pigs indicated that fexofenadine antagonized histamine-induced skin wheals in a dose-dependent manner. Fexofenadine and terfenadine antagonized the contractile effects of histamine in the guinea pig ileum in vitro. In this model, fexofenadine was found to be a more selective histamine antagonist than terfenadine.
Fexofenadine inhibited antigen-induced bronchospasm in sensitized guinea pigs and, at high doses (>100-fold higher than those required for antihistaminic activity), inhibited histamine release from peritoneal mast cells of the rat. In laboratory animals, no anticholinergic or alpha-1-adrenergic receptor blocking effects were observed. Radiolabelled tissue distribution studies in rat indicated that fexofenadine does not cross the blood-brain barrier.
Fexofenadine is not associated with significant ECG abnormalities. Studies have shown that fexofenadine does not affect the action potential or ion channel currents (IK, ICa, INa) in either guinea pig or neonatal rat myocytes. Fexofenadine was 583 times less potent than terfenadine in blocking a delayed rectifier potassium channel cloned from human heart. Additionally, doses of fexofenadine ten times greater than the dose of terfenadine that produces prolongation of QTc intervals do not prolong QTc intervals in anaesthetized rabbits and conscious dogs.
Clinical Trials: An escalating acute dose study demonstrated antihistaminic activity via skin wheal and flare inhibition at doses ranging from 40 mg to 800 mg, with maximum inhibition reaching a plateau at a dose of 130 mg. An escalating repeat dose study demonstrated increasing skin flare inhibition at twice daily doses ranging from 20 mg to 690 mg. During both acute dose and repeat dose studies, an antihistaminic effect was observed within one hour, achieving maximum effect within 2-4 hours and lasting a minimum of 12 hours. There was no evidence of tolerance to these effects after 28 days of dosing.
In dose ranging studies, fexofenadine HCl was shown to relieve the symptoms of seasonal allergic rhinitis, significantly reducing total symptom scores (including scores for sneezing, rhinorrhoea, itchy nose, palate and/or throat, and itchy, watery, red eyes) over a dosage range of 40 mg to 240 mg twice daily. In a double-blind, placebo-controlled trial of 208 patients with chronic idiopathic urticaria, fexofenadine HCl 180 mg and 240 mg once daily for 6 weeks were found to significantly reduce total symptom scores (number of wheals (hives) and pruritus). In a double-blind, placebo-controlled clinical efficacy study involving 821 patients with seasonal allergic rhinitis, fexofenadine HCl 120 mg and 180 mg once daily were found to be significantly superior to placebo in relieving symptoms of seasonal allergic rhinitis, including sneezing, rhinorrhoea, itchy nose, palate and/or throat, itchy, red or watery eyes and nasal congestion, after 24 hours. There was no statistically significant difference in efficacy between the two doses of fexofenadine, however the 180 mg dose did show a trend toward greater reduction in the mean total symptom score.
In a double-blind, placebo-controlled study, 861 patients aged 12-65 years were randomized to receive either 120 mg fexofenadine or 180 mg fexofenadine or placebo, once daily for a 2-week period. The primary efficacy measure was change from baseline of average total symptom score. Both doses provided significant (p ≤ 0.05) improvement in symptoms of seasonal allergic rhinitis, compared to placebo. While there was no statistically significant difference in efficacy between the two doses, the 180 mg dose showed a trend toward greater reduction in the average total symptom score.
In a double-blind, placebo-controlled study investigating quality-of-life, 845 patients aged 12-65 years were randomized to receive 120 mg fexofenadine or 180 mg fexofenadine or placebo once daily for a 2-week period. The primary efficacy measures were change from baseline in a quality-of-life score and in a work / activity impairment score. Patients receiving either 120 mg or 180 mg dose reported a significant (p ≤ 0.006) improvement in overall quality-of-life score and a significant (p ≤ 0.004) reduction in work / activity impairment score, compared to placebo. No statistical comparison was made between the effects of the two doses of fexofenadine.
The incidence of drowsiness in controlled clinical seasonal allergic rhinitis trials was similar when comparing patients treated with fexofenadine and placebo. There was no dose-related increase in drowsiness.
The effects of fexofenadine on the QTc interval have been investigated in a variety of studies at doses up to 800 mg/day. There were no statistically significant differences in QTc interval between fexofenadine- and placebo-treated patients. Similarly, there were no statistically significant differences from placebo or dose-related changes in other ECG parameters as a result of fexofenadine treatment. Also, no statistically significant change in QTc intervals was observed in long-term studies in healthy subjects given fexofenadine HCl 60 mg twice daily for 6 months and 240 mg once daily for 12 months, when compared to placebo.
Interaction studies in healthy volunteers between fexofenadine and erythromycin or ketoconazole demonstrated that although the plasma AUC for fexofenadine increased approximately 2-3 fold, there were no significant effects on mean or maximal QTc, nor were there any effects on the incidence of adverse events. Although these plasma levels were above those seen with the recommended dose, they were within the range of plasma levels achieved in controlled dose ranging clinical trials. Fexofenadine had no effect on the pharmacokinetics of erythromycin or ketoconazole (see Interactions).
Across the clinical trials, patients between the ages of 12 to 16 years have received doses ranging from 20 mg to 240 mg twice daily. Adverse events were similar in this group compared to patients above the age of 16 years.
Pharmacokinetics: Fexofenadine HCl is rapidly absorbed into the body following oral administration, with tmax occurring approximately 1-3 hours post-dose. Following administration of a single 60 mg oral dose to healthy volunteers, fexofenadine HCl was rapidly absorbed, with a mean Cmax of 209 ng/mL. Following the administration of single oral doses of 120 mg and 180 mg fexofenadine HCl, the mean Cmax values were approximately 427 ng/mL and 494 ng/mL, respectively.
The absolute bioavailability following fexofenadine HCl administration was estimated to be 33%. Co-administration with food has no clinically significant effect on the absorption of fexofenadine HCl.
The single and multiple dose pharmacokinetics of fexofenadine are linear for oral doses up to 120 mg bd. A dose of 240 mg bd produced a slightly greater than proportional increase (8.8%) in steady-state area under the curve, indicating that fexofenadine pharmacokinetics are practically linear at daily doses between 40 mg and 240 mg. Fexofenadine is 60% to 70% bound to plasma proteins.
Fexofenadine undergoes negligible metabolism. Following a single radiolabelled 60 mg oral dose, approximately 80% and 11% of the total [14C]-fexofenadine dose was excreted in faeces and urine, respectively.
The plasma concentration vs. time profiles of fexofenadine follow a bi-exponential decline with a mean terminal elimination half-life ranging from 14 to 15 hours following multiple dosing.
The pharmacokinetics of fexofenadine in seasonal allergic rhinitis patients are similar to those in healthy subjects.
Studies indicated that females may be exposed to higher plasma levels than males, however, there was no indication of any difference in efficacy or in the frequency of adverse events reported. Elderly patients, patients with hepatic impairment and patients with cardiac disease exposed to fexofenadine by administration of terfenadine showed no statistically significant differences in pharmacokinetic parameters for fexofenadine compared to healthy individuals. Although peak plasma level and half-life were increased 68% and 15%, respectively, in elderly patients and 54% and 19%, respectively, in patients with renal disease, regardless of disease severity, these levels are within the range of plasma levels shown to be tolerated in short-term dose ranging trials.
The pharmacokinetics of fexofenadine in children and adults are similar, including tmax, clearance (corrected for body surface area), t1/2 and volume of distribution, because fexofenadine undergoes negligible metabolism, with 80% of the dose being eliminated unchanged in the faeces. In contrast, other H1-receptor antagonists, which are extensively metabolized in the hepatic cytochrome P450 system, usually have shorter half-life values in children than adults.
In children, studies indicate that 30 or 60 mg fexofenadine suppresses the histamine-induced wheal and flare within 1 to 2 hours, with both doses producing similar mean maximal suppression.
A dose of 5 mL of Telfast Oral Suspension Pediatric containing 30 mg of fexofenadine HCl is bioequivalent to a 30 mg dose of Telfast tablets. Following oral administration of a 30 mg dose of Telfast Oral Suspension to healthy adult subjects, the mean Cmax was 118.0 ng/mL and occurred at approximately 1.0 hour.
