Fexofenadine

226.9 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

225.55 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Molecular weight is 538.13. 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 /Hydrochloride/

Increased concentrations of fexofenadine have been reported in 2 controlled drug interaction studies in healthy individuals receiving 120 mg of fexofenadine hydrochloride twice daily concomitantly with erythromycin dosages of 500 mg every 8 hours or ketoconazole 400 mg once daily. In these studies, area under the plasma-concentration time curve (AUC) of fexofenadine increased by 109 or 164% following concomitant administration with erythromycin or ketoconazole, respectively, while peak plasma concentrations of fexofenadine increased by 82 or 135%, respectively. However, no clinically important adverse effects or changes in the QT interval corrected for rate (QTc) were reported after concomitant administration of erythromycin or ketoconazole with fexofenadine.

Administration of a single 120-mg dose (2 capsules of 60 mg) of fexofenadine hydrochloride within 15 minutes of administration of an aluminum and magnesium hydroxides antacid (Maalox) decreased the AUC and peak plasma concentration of fexofenadine by 41 and 43%, respectively. Therefore, the manufacturer states that fexofenadine (alone or in fixed combination with pseudoephedrine hydrochloride) should not be taken closely in time with antacids containing aluminum and magnesium.

Fruit (grapefruit, orange, apple) juices may reduce bioavailability and systemic exposure of fexofenadine. In clinical studies, the size of wheal and flare was substantially larger when fexofenadine hydrochloride was administered with grapefruit juice or orange juice compared with water; based on literature reports, the same effects may be extrapolated to other fruit juices such as apple juice. The clinical importance of these observations is unknown. Based on a population pharmacokinetic analysis of combined data from the studies using concomitant grapefruit juice or orange juice with data from a bioequivalence study, bioavailability of fexofenadine was reduced by 36%. Therefore, to maximize the effects of fexofenadine, the manufacturer recommends that the drug be administered with water.

Fexofenadine use is not generally associated with liver enzyme elevations but terfenadine, a second generation antihistamine that is metabolized in part to fexofenadine, was the attributed cause of several reported cases of clinically apparent liver injury. Terfenadine was also linked to cardiac arrhythmias and prolongation of the QTc interval for which reason it was withdrawn from use in 1997, just as fexofenadine was introduced. Liver injury from terfenadine typically arose after 1 to 5 months and was associated with a hepatocellular pattern of liver enzyme abnormalities without immunoallergic or autoimmune features. Fexofenadine has not been linked to similar cases of cardiac arrhythmias or liver injury.

The most common dose-dependent adverse drug reactions associated with fexofenadine include drowsiness, fatigue, and dry mouth. In addition, post-marketing surveillance has reported rare occurrences of Stevens-Johnson syndrome or toxic epidermal necrolysis induced by fexofenadine.

Signs and Symptoms of Overdose

Like other H1-blockers, Fexofenadine competes with free histamine for binding at H1-receptors in the GI tract, large blood vessels, and bronchial smooth muscle. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms (eg. nasal congestion, watery eyes) brought on by histamine. Fexofenadine exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic or beta-adrenergic-receptor blocking effects.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

fexofenadine

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenesis was seen in mice and rats receiving oral terfenadine (the parent drug of fexofenadine; no longer commercially available in the US) dosages up to 150 mg/kg daily for 18 and 24 months, respectively, resulting in fexofenadine exposure levels calculated to be of 2-3 times the maximum recommended daily oral human dosage.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats and rabbits using oral terfenadine dosages up to 300 mg/kg resulting in fexofenadine exposure levels calculated to be about 3-4 and 25-31 times, respectively, those resulting from the maximum recommended daily oral human dosage of fexofenadine hydrochloride in adults have not revealed evidence of teratogenicity.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in mice receiving fexofenadine doses up to 3730 mg/kg (approximately 10-15 times the maximum recommended daily oral human dosage of fexofenadine hydrochloride in adults) have not revealed evidence of adverse or teratogenic effects during gestation.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in male and female mice receiving fexofenadine doses up to 4438 mg/kg (approximately 10-15 times the maximum recommended daily oral human dosage of fexofenadine hydrochloride in adults) have not revealed evidence of impaired fertility. Reproduction studies in rats using terfenadine dosages of 150 mg/kg (resulting in fexofenadine exposure levels calculated to be about 3-4 times those resulting from the maximum recommended daily oral human dosage of fexofenadine hydrochloride), revealed dose-related decreases in implantation and an increased incidence of postimplantation losses.[McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34]

For more Non-Human Toxicity Excerpts (Complete) data for FEXOFENADINE (6 total), please visit the HSDB record page.

The terminal elimination half-life is approximately 11-15 hours.

Following oral administration of 60 mg of fexofenadine hydrochloride twice daily in healthy individuals, the mean elimination half-life of the drug at steady state reportedly is about 14.4-14.6 hours; mean elimination half-life reportedly was similar in geriatric adults (65 years of age or older) who received a single 80-mg oral dose of fexofenadine hydrochloride.

... Elimination half-life was about 18 hours in fasting children (mean age: 8-11.6 years) who received single oral 30- or 60-mg doses of fexofenadine hydrochloride as capsules.

In patients with mild (creatinine clearance of 41-80 mL/minute) to severe (creatinine clearance of 11-40 mL/minute) renal impairment, mean elimination half-lives were 59 and 72% longer than those observed in healthy individuals, respectively.

In patients undergoing dialysis (creatinine clearance of 10 mL/minute or less), elimination half-life was 31% longer than in healthy individuals.

Fexofenadine is very minimally metabolized, with only 5% of an ingested dose undergoing hepatic metabolism. The only identified metabolites are a methyl ester of fexofenadine (3.6% of the total dose) and MDL 4829 (1.5% of the total dose). The enzymes responsible for this metabolism have not been elucidated.

About 5% of a single oral dose of fexofenadine is metabolized.

Negligible amounts of fexofenadine (about 0.5-1.5% of a dose) are metabolized in the liver by the cytochrome P-450 microsomal enzyme system to an inactive metabolite, while about 3.5% of a fexofenadine dose is metabolized by a second metabolic pathway (unrelated to the cytochrome P-450 microsomal enzyme system) to the methyl ester derivative of fexofenadine. The methyl ester metabolite of fexofenadine is found only in feces, and it has been suggested that the intestinal flora probably are involved in this metabolism.

Approximately 5% of the total dose is metabolized, by cytochrome P450 3A4 and by intestinal microflora. Half Life: 14.4 hours

E6582LOH6V

FEXOFENADINE

Mechanisms of Action [MoA] - Histamine H1 Receptor Antagonists

Established Pharmacologic Class [EPC] - Histamine-1 Receptor Antagonist

Fexofenadine is a Histamine-1 Receptor Antagonist. The mechanism of action of fexofenadine is as a Histamine H1 Receptor Antagonist.

Agents that are used to treat allergic reactions. Most of these drugs act by preventing the release of inflammatory mediators or inhibiting the actions of released mediators on their target cells. (From AMA Drug Evaluations Annual, 1994, p475)

A class of non-sedating drugs that bind to but do not activate histamine receptors (DRUG INVERSE AGONISM), thereby blocking the actions of histamine or histamine agonists. These antihistamines represent a heterogenous group of compounds with differing chemical structures, adverse effects, distribution, and metabolism. Compared to the early (first generation) antihistamines, these non-sedating antihistamines have greater receptor specificity, lower penetration of BLOOD-BRAIN BARRIER, and are less likely to cause drowsiness or psychomotor impairment.

Fexofenadine is rapidly absorbed following oral administration and its absolute bioavailability is approximately 33%. The Tmax following oral administration is approximately 1-3 hours. The steady-state AUCss(0-12h) and Cmax following twice daily dosing of 60mg are 1367 ng/mL.h and 299 ng/mL, respectively. Fexofenadine AUC is decreased by >20% when coadministered with fruit juices (e.g. apple, orange, grapefruit) due to their inhibition of OATP transporters - for this reason, prescribing information recommends administering fexofenadine only with water. Similarly, coadministration of fexofenadine with a high-fat meal appears to decrease AUC and Cmax by >20%.

Approximately 80% of an ingested dose is eliminated in the feces, likely largely unchanged due to fexofenadine's limited metabolism, and 11% is eliminated in the urine. The principal pathways of fexofenadine elimination are biliary and renal.

The volume of distribution is approximately 5.4-5.8 L/kg.

The oral clearance of fexofenadine is approximately 50.6 L/h and the renal clearance is approximately 4.32 L/h.

Fexofenadine hydrochloride is rapidly absorbed from the GI tract following oral administration. Following oral administration of two 60-mg fexofenadine hydrochloride capsules, peak plasma concentrations are achieved in about 2.6 hours. Following oral administration of a single 60-mg capsule or 60- or 180-mg conventional tablet in healthy individuals, mean peak plasma concentrations were 131, 142, and 494 ng/mL, respectively. In healthy men, peak plasma concentrations of 167 ng/mL were achieved within 1.42 hours following oral administration of 60-mg fexofenadine hydrochloride doses every 12 hours for 9 doses.

Following oral administration of fexofenadine hydrochloride capsules in fasting children (mean age: 8-11.6 years) with a history of allergic rhinitis with or without mild asthma, peak plasma fexofenadine concentrations of about 178 or 286 ng/mL were attained in approximately 2.4 hours after a 30- or 60-mg dose, respectively.