AHFS Class:

• Second Generation Antihistamines 4:08

Generic Name(s):

• Fexofenadine Hydrochloride

Associated Monographs

• Antihistamines General Statement

Fexofenadine, a second-generation antihistamine, is the active carboxylic acid metabolite of terfenadine.1,2,3,18,79,80

Fexofenadine shares the uses of other antihistamines, including the management of allergic rhinitis1,2,36,39,77,79,80,81,88 and chronic idiopathic urticaria.1,70,79 For additional information on these and other uses of antihistamines, see Uses in the Antihistamines General Statement 4:00.

Fexofenadine is the active carboxylic acid metabolite of terfenadine (no longer commercially available in the US).1,2,3,18 Fexofenadine is thought to provide essentially all the therapeutic benefits of terfenadine16,17,37 while avoiding the serious cardiotoxic and drug interaction risks of the parent drug,1,2,15,16,17,36,37,41,66,67 and therefore is considered a relatively safe alternative to terfenadine.16,17,37 Although other relatively nonsedating (second generation) antihistamines that lack the cardiotoxic and drug interaction potentials of terfenadine also are commercially available in the US, individual patients vary in their response to antihistamines,16 and a specific antihistamine that provides dramatic relief without adverse effects to one patient may be ineffective or poorly tolerated in another.16 Trial of various antihistamines may be necessary to determine which drug will cause relief while causing minimal adverse effects.70

Allergic Rhinitis

Fexofenadine alone or in fixed combination with pseudoephedrine hydrochloride is used to provide symptomatic relief of seasonal allergic rhinitis (e.g., hay fever) in adults and children 6 years of age and older or in adults and children 12 years and older, respectively.1,2,36,39,77,79,80,81,88 Fexofenadine provides symptomatic relief of rhinorrhea,1,34,41,77,88 sneezing,1,34,41,77,88 oronasopharyngeal itching,1,34,41,77,88 and red, itching, watery eyes.1,34,41,77,88 Extended-release tablets containing fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride also provide symptomatic relief of nasal congestion.77,88 However, it is recommended that the fixed combination generally be used only when both the antihistaminic and nasal decongestant activity of the combination preparation are needed concurrently.77,88

Antihistamines are not curative and merely provide palliative relief; since seasonal allergic rhinitis may be a chronic, recurrent condition, successful therapy often may require long-term intermittent use of these drugs.4,6,7 In the treatment of seasonal allergic rhinitis, antihistamines are more likely to be beneficial when therapy is initiated at the beginning of the hay fever season when pollen counts are low.7,28,29,30,31 Antihistamines are less likely to be effective when pollen counts are high, when pollen exposure is prolonged, and when nasal congestion is prominent.7,29,33 Chronic nasal congestion and headache caused by edema of the paranasal sinus mucosa are often refractory to antihistamine therapy.6,7,28,29,32 The drugs generally are not effective in relieving symptoms of nasal obstruction.6,7,28,35

Safety and efficacy of fexofenadine in the management of seasonal allergic rhinitis were established in several 2-week multicenter, randomized, double-blind, placebo-controlled studies in patients with seasonal allergic rhinitis 12-68 years of age.1,34,41 In these studies, treatment with fexofenadine hydrochloride (administered in a dosage of 60 mg twice daily or 180 mg once daily) was more effective than placebo in providing symptomatic relief of rhinorrhea, sneezing, oronasopharyngeal itching, and itching, red, watery eyes.1,34,41 In addition, results of one 12-week clinical study in patients with seasonal allergic rhinitis indicate that fexofenadine hydrochloride (given in a dosage of 60 mg twice daily) is at least as effective as loratadine (given in a dosage of 12 mg daily) in providing relief of rhinorrhea and other subjective symptoms of such rhinitis.70,71 The efficacy of fexofenadine reportedly is not affected by age, gender, or race.1

Safety and efficacy of the extended-release fixed-combination preparation containing 60 mg of fexofenadine hydrochloride and 120 mg of pseudoephedrine hydrochloride were established in a 2-week randomized, double-blind, active-controlled study in patients 12-65 years of age with seasonal allergic rhinitis.77,82 In this study, treatment with the fixed-combination tablets twice daily was more effective than treatment with either drug alone in reducing the intensity of sneezing, rhinorrhea, oronasopharyngeal itching, itchy/red/watery eyes, and nasal congestion.77,82 Clinical safety and efficacy studies have not been conducted with the extended-release fixed-combination preparation containing 180 mg of fexofenadine hydrochloride and 240 mg of pseudoephedrine hydrochloride.88 Efficacy of this preparation in the management of seasonal allergic rhinitis is based on an extrapolation of the demonstrated efficacy of fexofenadine hydrochloride 180 mg and the nasal decongestant properties of pseudoephedrine hydrochloride.88

Fexofenadine hydrochloride also is used to provide symptomatic relief in the treatment of seasonal allergic rhinitis in children 6 years of age and older.1 Efficacy of fexofenadine hydrochloride for symptomatic treatment of seasonal allergic rhinitis in children 6 years of age and older is based on a 2-week randomized, placebo-controlled study in children 6-11 years of age with seasonal allergic rhinitis and on extrapolation of the demonstrated efficacy of fexofenadine hydrochloride in patients 12 years of age and older and on pharmacokinetic comparisons in adults and children.1 Results of the 2-week multicenter, randomized, placebo-controlled study in 411 children 6-11 years of age with seasonal allergic rhinitis indicate that fexofenadine hydrochloride (administered in dosages of 15, 30, or 60 mg twice daily) is more effective than placebo in providing symptomatic relief of rhinorrhea, sneezing, oronasopharyngeal itching and red, itching, watery eyes; however, a dose-response relationship has not been observed.1 In this study, fexofenadine hydrochloride dosages of 60 mg twice daily did not appear to provide additional therapeutic benefit compared with fexofenadine hydrochloride dosages of 30 mg twice daily.1 In addition, a 30-mg dose in children was reported to be comparable to a 60-mg dose in adults.1 Recommended pediatric dosages are based on cross-study comparisons of the pharmacokinetics of fexofenadine in adults and children and on safety profiles of the drug from studies in adults and children at recommended or higher doses.1

Chronic Idiopathic Urticaria

Fexofenadine hydrochloride is used for the management of pruritus, erythema, and urticaria associated with chronic idiopathic urticaria in adults and children 6 years of age and older.1,70,79

Results of two 4-week multicenter, randomized, placebo-controlled studies in 726 patients with chronic idiopathic urticaria 12-70 years of age indicate that fexofenadine hydrochloride (administered in dosages of 20, 60, 120, and 240 mg twice daily) is more effective than placebo in decreasing manifestations of urticaria, relieving associated pruritus, and reducing whealing.1 Symptom reduction was greater than and efficacy was maintained over the entire 4-week treatment period with fexofenadine hydrochloride dosages of 60, 120, and 240 mg twice daily, but the 120- and 240-mg twice-daily dosages provide no additional clinical benefit over that reported with the 60-mg twice-daily dosage.1

Efficacy of fexofenadine hydrochloride for the management of chronic idiopathic urticaria in children 6 years of age and older is based on extrapolation of the demonstrated efficacy of fexofenadine hydrochloride in adults and the likelihood that the disease course, pathophysiology, and drug activity are substantially similar between the 2 populations.1

Common Cold

Although antihistamines frequently are used for symptomatic relief in the common cold,6,43,44,45,46,47,48,49,50,51,68,69 evidence of effectiveness for the drugs remains to be established.6,27,43,44,45,46,47,48,49,50,51,68 Antihistamines cannot prevent, cure, or shorten the course of the common cold,44,45,46,47,48,54 but may provide some symptomatic relief.32,43,45,54,55,68,69 Conventional (prototypical, first generation) antihistamines (e.g., those with anticholinergic activity) are considered effective in relieving rhinorrhea and sneezing associated with the common cold,32,45,54,55,68 but evidence of efficacy in relieving oronasopharyngeal itching, lacrimation, or itching eyes associated with this condition currently is lacking.32 Relatively nonsedating (second generation) antihistamines (e.g., terfenadine) do not appear to be effective in relieving rhinorrhea associated with the common cold, suggesting that histamine is not a principal mediator of this manifestation.53,57,68 The extent to which histamine contributes to other manifestations of the common cold currently is unclear, but pathogenesis of the full constellation of symptoms that constitute the common cold appears to be complex, involving a number of mediators and neurologic mechanisms.52,53,56,59,60 In several studies, terfenadine (the parent drug of fexofenadine) was no more effective than placebo in providing symptomatic relief of the common cold.51,57,58

Administration

Fexofenadine hydrochloride is administered orally.1,2 The manufacturer states that when fexofenadine hydrochloride is given alone (i.e., not in fixed combination with pseudoephedrine hydrochloride) the drug may be given without regard to meals.8 Since absorption and peak plasma concentrations of fexofenadine are decreased by concomitant administration of an aluminum and magnesium hydroxides antacid (Maalox^®) (see Pharmacokinetics: Absorption and see Drug Interactions: Antacids), the manufacturer recommends that the drug not be taken closely in time with an antacid containing aluminum and magnesium.1 Since food appears to substantially affect the rate and extent of absorption of fexofenadine hydrochloride when administered as the extended-release tablets of the drug in fixed combination with pseudoephedrine hydrochloride, the manufacturer states that such extended-release tablets should be administered on an empty stomach with water.77,88 (See Pharmacokinetics: Absorption and see Drug Interactions: Fruit Juices.) Extended-release tablets containing fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride should be swallowed intact, and patients should be instructed not to break, crush, or chew such tablets.77,88

Dosage

Allergic Rhinitis

For symptomatic relief of seasonal allergic rhinitis, the usual dosage of fexofenadine hydrochloride for adults and children 12 years of age and older is 60 mg twice daily or 180 mg once daily.1,2,39 Fexofenadine hydrochloride dosages exceeding 60 mg twice daily (up to a dosage of 240 mg twice daily) do not appear to provide additional therapeutic benefit.1 When one of the fixed combinations containing fexofenadine hydrochloride with pseudoephedrine hydrochloride is used for symptomatic relief of allergic rhinitis in adults and children 12 years of age and older, the usual dosage of fexofenadine hydrochloride is 60 mg twice daily (as Allegra-D^® 12 Hour)77 or 180 mg once daily (as Allegra-D^® 24 Hour).77

For symptomatic relief of seasonal allergic rhinitis, the usual dosage of fexofenadine hydrochloride for children 6 to younger than 12 years of age is 30 mg twice daily.1

Although peak plasma fexofenadine concentrations increased by 99% in healthy adults 65 years of age and older when compared with those in younger adults, there appears to be no evidence of age-related differences in the mean elimination half-lives between geriatric and younger adults.1,2,3 In addition, limited data indicate that the safety profile of the drug in adults 60-68 years of age is similar to that in adults younger than 60 years of age.1,2,3 Therefore, dosage adjustment of fexofenadine hydrochloride solely on the basis of age generally is not required for healthy geriatric patients.1,2 However, the possible need for dosage adjustment in geriatric patients should be considered for those with decreased renal function since clearance of the drug may be decreased and half-life prolonged in such patients.1,2,8 (See Dosage: Dosage in Renal and Hepatic Impairment, in Dosage and Administration.)

Chronic Idiopathic Urticaria

For the management of chronic idiopathic urticaria, the usual dosage of fexofenadine hydrochloride for adults and children 12 years of age and older is 60 mg twice daily.1 The usual dosage for children 6 to younger than 12 years of age is 30 mg twice daily.1

Dosage in Renal and Hepatic Impairment

Adjustment of fexofenadine hydrochloride dosage may be necessary in patients with renal impairment.1,2 Peak plasma fexofenadine concentrations increased by 87 or 111%, and elimination half-life increased by 59 or 72% in patients with mild (e.g., creatinine clearance of 41-80 mL/minute) or severe (creatinine clearance of 11-40 mL/minute) renal impairment, respectively, when compared with those observed in healthy individuals.1,2 In addition, peak plasma fexofenadine concentration increased by 82% and elimination half-life increased by 31% in those on hemodialysis (creatinine clearance of 10 mL/minute or less) compared with healthy individuals.1,2

The manufacturer states that adults and children 12 years of age and older with impaired renal function or those on hemodialysis should receive an initial fexofenadine hydrochloride dosage of 60 mg daily (either given alone or in fixed combination with 120 mg of pseudoephedrine hydrochloride [Allegra-D^® 12 Hour]).1,2,77 The fixed-combination preparation containing 180 mg of fexofenadine hydrochloride and 240 mg of pseudoephedrine hydrochloride (Allegra-D^® 24 Hour) generally should be avoided in patients with renal impairment because of a possible risk of accumulation of pseudoephedrine.88

Children 6 to younger than 12 years of age with impaired renal function should receive an initial fexofenadine hydrochloride dosage of 30 mg daily.1

Since the pharmacokinetics of fexofenadine do not appear to be altered in patients with hepatic impairment, the manufacturer states that dosage adjustment is not necessary in such patients.1,2,79 The manufacturer of Allegra-D^® 12 Hour and Allegra-D^® 24 Hour does not make specific recommendations for dosage adjustment in patients with hepatic impairment, although it is not known if pharmacokinetics of pseudoephedrine are altered in patients with hepatic impairment.77,88

Although fexofenadine is the active metabolite of terfenadine (the parent drug of fexofenadine; no longer commercially available in the US), fexofenadine does not share the cardiotoxic and drug interaction potentials of terfenadine.15,16,17,37,41,66,67 In addition, although experience with fexofenadine is far less extensive than with terfenadine, no new adverse effects, not already associated with terfenadine, would be expected with fexofenadine since most patients receiving terfenadine have been in fact exposed principally to fexofenadine as a result of extensive first-pass metabolism of the parent drug in the liver.16 However, as with any drug, certain drug-induced adverse effects (e.g., those dependent on individual susceptibilities) usually are not detected for several years after marketing, since the number of patients exposed during clinical trials is small relative to the total number of individuals exposed to the drug during postmarketing surveillance.78

In placebo-controlled studies, adverse effects reported in adults and children 12 years of age and older with chronic idiopathic urticaria are similar to those in patients with seasonal allergic rhinitis.1 During controlled clinical studies in patients 12 years of age and older receiving oral fexofenadine hydrochloride dosages of 20-240 mg twice daily or 120 or 180 mg once daily, the incidence of fexofenadine-induced adverse effects was similar to that reported with placebo.1,2,16,34,41,77,79,88 The incidence of adverse effects (e.g., drowsiness) was not affected by dose, age, gender, or race.1,2 Discontinuance of fexofenadine therapy because of adverse events was reported in 2.2% of patients receiving the drug compared with 3.3% of those receiving placebo.2,79

Results of a clinical study indicate that adverse reactions reported to date with extended-release tablets containing fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride have been similar to those reported in patients receiving either drug as individual preparations.77 In one clinical trial, discontinuance of therapy was reported in 3.7, 0.5, or 4.1% of patients receiving the extended-release tablets containing fexofenadine hydrochloride (60 mg) in fixed combination with pseudoephedrine hydrochloride (120 mg) twice daily, fexofenadine hydrochloride alone, or pseudoephedrine hydrochloride alone, respectively.77 Many of the adverse effects (e.g., insomnia, headache, nausea, dry mouth, dizziness, agitation, nervousness, anxiety, palpitation) occurring in patients receiving the commercially available fixed combination were adverse effects that were reported mainly in patients receiving pseudoephedrine hydrochloride alone.77

Nervous System Effects

In controlled clinical studies in patients 12 years of age and older with allergic rhinitis receiving oral fexofenadine hydrochloride dosages of 60 mg twice daily or placebo, drowsiness or fatigue occurred in 1.3% of patients, compared with 0.9% of those receiving placebo.1,79 In these studies in patients receiving fexofenadine hydrochloride dosages of 180 mg once daily (as conventional tablets) or placebo, headache was reported in 10.6 or 7.5% of patients, respectively.1,88 In controlled studies in children 6-11 years of age with seasonal allergic rhinitis receiving fexofenadine hydrochloride dosages of 30 mg twice daily or placebo, headache was reported in 7.2 or 6.6% of patients, respectively, while pain was reported in 2.4 or 0.4% of patients, respectively.1 In clinical trials in patients receiving the extended-release tablets containing fexofenadine hydrochloride (60 mg) in fixed combination with pseudoephedrine hydrochloride (120 mg), headache occurred in 13% of patients receiving the fixed combination, 11.5% of those receiving fexofenadine hydrochloride alone, and 17.4% of those receiving pseudoephedrine hydrochloride alone.77 The incidence of headache was higher in patients receiving placebo than in those receiving fexofenadine.1,34,79

In studies of patients receiving the extended-release tablets containing fexofenadine hydrochloride (60 mg) in fixed combination with pseudoephedrine hydrochloride (120 mg) twice daily, insomnia occurred in 12.6% of patients receiving the combination, 3.2% of those receiving fexofenadine hydrochloride alone, and 13.3% of those receiving pseudoephedrine hydrochloride alone.77 Dizziness or agitation occurred in 1.9 or 1.9% of patients receiving the combination, respectively, 0 or 0% of those receiving fexofenadine hydrochloride alone, respectively, and 3.2 or 1.4% of those receiving pseudoephedrine hydrochloride alone, respectively.77 In addition, nervousness or anxiety each occurred in 1.4% of patients receiving the combination, 0.5 or 0% of those receiving fexofenadine hydrochloride alone, respectively, and 1.8 or 1.4% of those receiving pseudoephedrine hydrochloride alone, respectively.77

In controlled studies in adults and children 12 years of age and older with chronic idiopathic urticaria receiving fexofenadine hydrochloride dosages of 60 mg twice daily or placebo, dizziness was reported in 2.2 or 0.6%, respectively, while drowsiness was reported in 2.2% or 0% respectively.1

Sleep disorder, insomnia, or paroniria has occurred in patients receiving fexofenadine hydrochloride.1,77,88

GI Effects

During controlled clinical studies, nausea and dyspepsia were reported in 1.6 and 1.3%, respectively, of patients receiving oral fexofenadine hydrochloride dosages of 60 mg twice daily versus 1.5 and 0.6%, respectively, of those receiving placebo.1,79 In studies of patients receiving extended-release dosage forms of fexofenadine hydrochloride (60 mg) in fixed combination with pseudoephedrine hydrochloride (120 mg), nausea or dry mouth occurred in 7.4 or 2.8% of patients receiving the combination, respectively, 0.5 or 0.5% of those receiving fexofenadine hydrochloride alone, respectively, and 5 or 5.5% of those receiving pseudoephedrine hydrochloride alone, respectively.77 Dyspepsia or abdominal pain occurred in 2.8 or 1.4% of patients receiving the combination, respectively, 0.5 or 0.5% of those receiving fexofenadine hydrochloride alone, respectively, and 0.9 or 0.5% of those receiving pseudoephedrine hydrochloride alone, respectively.77

Cardiac Effects

Clinical data from over 2000 patients indicate that fexofenadine hydrochloride lacks the cardiotoxic potential of its parent drug terfenadine.1,2,15,16,17,36,41,66,67,79 In 714 patients with seasonal allergic rhinitis, fexofenadine hydrochloride dosages of 60-240 mg twice daily were not associated with statistically significant mean increases in the QT interval corrected for rate (QT_c) in controlled clinical studies.1,2,34,39,70,77,79 In addition, in 231 healthy individuals, fexofenadine hydrochloride dosages of 240 mg given once daily for 1 year also were not associated with statistically significant increases in the mean QT_c.1 Even at dosages exceeding these (e.g., up to 400 mg twice daily for 6 days in 40 patients, up to 690 mg twice daily for about 1 month in 32 patients, up to 800 mg given in a single dose in 87 patients), statistically significant mean increases in the QT_c or other ECG abnormalities have not been reported in healthy adults or patients with seasonal allergic rhinitis.1,70,79 In children 5-11 years of age, fexofenadine hydrochloride dosages of up to 60 mg twice daily were not associated with statistically significant treatment- or dose-related increases in QT_c in 2 placebo-controlled studies.1,8 In addition, no statistically significant increases in the mean QT_c interval have been reported in patients with seasonal allergic rhinitis receiving the commercially available extended-release tablets containing 60 mg of fexofenadine hydrochloride in fixed combination with 120 mg of pseudoephedrine hydrochloride for about 2 weeks when compared with those receiving fexofenadine hydrochloride (60 mg twice daily) or pseudoephedrine hydrochloride (120 mg twice daily) as individual drugs.77

In one patient with a preexisting increased QT_c interval (494 msec) and cardiovascular abnormalities and risk factors, additional prolongation of the QT_c interval (to 532 msec) and syncope occurred 2 months after discontinuance of carvedilol and initiation of fexofenadine hydrochloride 180 mg daily (without concomitant drug therapy).78 When fexofenadine hydrochloride was discontinued (for 5 days) the QT_c interval decreased to 489 msec,78 but the patient still experienced serious ventricular arrhythmias 4 days after discontinuance of the drug.70,84 Upon rechallenge with the same dosage of fexofenadine hydrochloride for 5 days, the QT_c interval increased again to 512 msec, and the patient experienced polymorphic ventricular tachycardia that rapidly progressed to ventricular fibrillation.78 Upon discontinuance of the drug, the QT_c interval decreased to 482 msec.78 Because additional increases in the QT_c interval occurred with rechallenge of fexofenadine hydrochloride, a causal relationship between these adverse cardiac effects and the drug was suggested.78 It should be considered, however, that this patient had a QT_c interval above normal limits while not receiving fexofenadine hydrochloride, and the patient was prone to developing increased QT_c intervals.78

The clinicians reporting this case state that the possibility of fexofenadine-induced increases in QT_c interval and potential ventricular arrhythmias should be considered in susceptible patients pending further accumulation of pharmacoepidemiologic data.78,85 However, the manufacturer questions a causal relationship in this case and, while the possibility of an effect cannot be excluded completely, the manufacturer does not share the concern of the clinicians that such a caution is needed in light of existing preclinical and clinical data showing no evidence of clinically important QT prolongation with the drug, even at high dosages.70,84

It has been suggested that the increased safety profile of fexofenadine compared with the parent drug results from the lack of fexofenadine-induced cardiotoxicity in addition to only minimal metabolism of fexofenadine in the liver by the cytochrome P-450 microsomal enzyme system.1,2,15,16,17,36,66,67,70,78 Evidence from animal models using fexofenadine have suggested that the apparent lack of cardiotoxic effects of the drug may have resulted at least in part from lack of blockade of the potassium channel involved in repolarization of cardiac cells (i.e., blockade of the delayed rectifier potassium current I_K).1,8,16,36,66,67 Prolongations in the QT_c interval were not reported in dogs receiving oral fexofenadine hydrochloride dosages of 10 mg/kg daily for 5 days or in rabbits receiving an IV fexofenadine hydrochloride dose of 10 mg/kg (resulting in plasma fexofenadine concentrations 28 or 63 times the therapeutic plasma concentrations in humans, respectively, based on a dosage of 60 mg of fexofenadine hydrochloride given twice daily).1,79 In addition, 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 the delayed rectifier potassium channel cloned from human heart at fexofenadine concentrations up to 10^-5 M (approximately equivalent to 32 times the therapeutic plasma concentrations in humans, based on a dosage of 60 mg of fexofenadine hydrochloride given twice daily).1,2

In studies of patients receiving the extended-release tablets containing fexofenadine hydrochloride (60 mg) in fixed combination with pseudoephedrine hydrochloride (120 mg) twice daily, palpitation occurred in 1.9% of patients receiving the combination, 0% of those receiving fexofenadine hydrochloride alone, and 0.9% of those receiving pseudoephedrine hydrochloride alone.77

Dermatologic and Sensitivity Reactions

Rash, urticaria, pruritus, and hypersensitivity reactions including angioedema, chest tightness, dyspnea, flushing, or anaphylaxis have been reported rarely in patients receiving fexofenadine hydrochloride.1,77

Other Adverse Effects

Viral infection (e.g., cold, influenza) or dysmenorrhea was reported in 2.5 or 1.5% of patients 12 years of age and older receiving fexofenadine hydrochloride in dosages of 60 mg twice daily, respectively.1,79 In controlled clinical studies in adults and children 12 years of age and older receiving fexofenadine hydrochloride dosages of 180 mg once daily or placebo, upper respiratory tract infection was reported in 3.2 or 3.1% of patients, respectively, while back pain was reported in 2.8 or 1.4% of patients, respectively.1

In studies of patients receiving the extended-release tablets containing fexofenadine hydrochloride (60 mg) in fixed combination with pseudoephedrine hydrochloride (120 mg) twice daily, throat irritation or upper respiratory infection occurred in 2.3 or 1.4% of patients receiving the combination, respectively, 1.8 or 0.9% of those receiving fexofenadine hydrochloride alone, respectively, and 0.5 or 0.9% of those receiving pseudoephedrine hydrochloride alone, respectively.77 In addition, back pain occurred in 1.9% of patients receiving the combination, 0.5% of those receiving fexofenadine hydrochloride alone, and 0.5% of those receiving pseudoephedrine hydrochloride alone.77

In controlled studies in children 6-11 years of age with seasonal allergic rhinitis receiving fexofenadine hydrochloride 30 mg twice daily, upper respiratory tract infection, coughing, accidental injury, fever, and otitis media occurred in 4.3, 3.8, 2.9, 2.4, and 2.4% of children, respectively, while these adverse effects were reported in 1.7, 1.3, 1.3, 0.9, and 0%, respectively, in those receiving placebo.1

In controlled studies in adults and children 12 years and older with chronic idiopathic urticaria receiving fexofenadine hydrochloride dosages of 60 mg twice daily or placebo, both back pain and sinusitis were reported in 2.2 or 1.1% of patients, respectively.1

Precautions and Contraindications

Although fexofenadine does not share the cardiotoxic potential of its parent drug terfenadine,1,2,15,16,17,36,37,41,66,67 fexofenadine has been associated with increased QT_c interval, syncope, and ventricular arrhythmia in at least one susceptible patient with preexisting cardiovascular risk.78 (See Cautions: Cardiac Effects.) In addition, although drug interactions between fexofenadine and certain drugs have been reported, fexofenadine does not share the drug interaction potential of terfenadine.1,2 (See Drug Interactions.) If a fixed-combination preparation containing fexofenadine hydrochloride with pseudoephedrine hydrochloride is used, the cautions, precautions, and contraindications associated with pseudoephedrine must be considered.77,88

Patients receiving preparations containing fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride should be instructed to take the drug only as prescribed and not to exceed the prescribed dosage.77,88 Patients also should be advised not to use other antihistamines or decongestants for self-medication .77,88 If nervousness, dizziness, or sleepiness occurs during therapy, patients should be advised to discontinue use of the fixed-combination preparation and consult a clinician.77,88 Patients also should be instructed to store the drug in a tightly closed container in a cool, dry place, and away from children.77,88 Patients receiving the extended-release fixed-combination preparation containing 60 mg of fexofenadine hydrochloride and 120 mg of pseudoephedrine hydrochloride (Allegra-D^® 12 Hour) should be informed that the inert tablet ingredients occasionally may be eliminated in feces in a form that may resemble the original tablet.77

Fexofenadine is contraindicated in patients who are hypersensitive to the drug or any ingredient in its formulation.1,77,88

Pediatric Precautions

Safety and efficacy of fexofenadine hydrochloride have not been established in children younger than 6 years of age.1,2 The safety of fexofenadine hydrochloride for symptomatic relief of seasonal allergic rhinitis in children 6-11 years of age is based on 2 placebo-controlled studies in which dosages of 30 mg twice daily of the drug were administered for 2 weeks.1 (See Uses.) The safety of fexofenadine hydrochloride for the management of chronic idiopathic urticaria in children 6-11 years of age is based on cross-study comparisons of the pharmacokinetics of fexofenadine in adults and children and on the safety profile of fexofenadine in both adults and children at recommended or higher dosages.1 Recommended pediatric doses are based on cross-study comparisons of the pharmacokinetics of fexofenadine in adults and children and on safety profiles of the drug from studies in adults and children at recommended or higher doses.1 In addition, fexofenadine hydrochloride (20-240 mg given twice daily for up to 2 weeks) has been used in adolescents 12-16 years of age, and adverse effects reported in this age group were similar to those reported in individuals older than 16 years of age.1

Safety and efficacy of fexofenadine in fixed combination with pseudoephedrine hydrochloride have not been established in children younger than 12 years of age, and use of such preparations (Allegra-D^® 12 Hour and Allegra-D^® 24 Hour) is not recommended in this age group.77,88 In addition, it should be noted that the doses of fexofenadine hydrochloride and pseudoephedrine hydrochloride in the fixed-combination preparations exceed those recommended for children younger than 12 years of age.77,88

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, OTC) preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.89,90 There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by the US Food and Drug Administration [FDA]) for the symptomatic treatment of cold and cough have not been established.89 Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of a the agency continues to assess safety and efficacy of these preparations in older children. Meanwhile, because children 2-3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age. FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in the Antihistamines General Statement 4:00.

Geriatric Precautions

Fexofenadine hydrochloride (20-240 mg given twice daily for up to 2 weeks) has been used in patients 60-68 years of age, and adverse effects reported in this age group were similar to those reported in younger adults.1,77

Clinical studies of fexofenadine hydrochloride capsules and conventional tablets and of extended-release tablets containing fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1,77,88 Although clinical experience generally has not revealed differences in responses between geriatric and younger patients to the drug, it should be considered that fexofenadine is substantially excreted by the kidneys and the risk of severe adverse reactions to the drug may be increased in patients with impaired renal function.1,77,88 Because geriatric patients may have decreased renal function, the manufacturer states that monitoring renal function may be useful and dosage should be selected with caution in these patients.1,77,88 In addition, it should be considered that geriatric patients receiving the extended-release tablets containing fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride may be especially sensitive to, and are more likely to have adverse effects from, administration of sympathomimetic amines than younger patients.77,88 For further information about the effects of pseudoephedrine in geriatric patients, see Cautions: Precautions and Contraindications in Pseudoephedrine 12:12.12.

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was seen when fexofenadine was tested in vitro for bacterial reverse mutation, CHO/HGPRT forward mutation, and rat lymphocyte chromosomal aberration assays.1,2 The drug also did not exhibit mutagenic potential in vivo in the mouse bone marrow micronucleus test.1 Mutagenic studies have not been performed using the fixed-combination tablets containing fexofenadine hydrochloride and pseudoephedrine hydrochloride.77,88

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.1,77,88 Carcinogenicity studies have not been performed using the fixed-combination tablets containing fexofenadine hydrochloride and pseudoephedrine hydrochloride.77,88

Pregnancy, Fertility, and Lactation

Pregnancy

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.77,88 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.1,77,88 However, in rats, oral 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 in adults (based on comparison of the AUC), were associated with decreased weight gain and neonatal survival in the pups.1,77,88

Reproduction studies in rats and rabbits using terfenadine and pseudoephedrine hydrochloride in a fixed-combination ratio of 1:2 at dosages of 150/300 (corresponding to fexofenadine AUCs of about 3-4 times the maximum recommended adult therapeutic value and to pseudoephedrine hydrochloride dosages about 10 times the maximum recommended human adult daily oral dosage, on a mg/m² basis) and 100/200 mg/kg daily (corresponding to fexofenadine AUCs of about 8-10 times the maximum recommended adult therapeutic value and to pseudoephedrine hydrochloride dosages about 15 times the maximum recommended human adult daily oral dosage, on a mg/m² basis), respectively, have revealed evidence of reduced fetal weight; delayed ossification with wavy ribs also was observed in rats receiving the drug at these dosages.77,88

There are no adequate and controlled studies to date using fexofenadine in pregnant women, and fexofenadine hydrochloride alone or in fixed combination with pseudoephedrine hydrochloride should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,77,88

Fertility

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.77,88 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.1 Reproduction studies to evaluate effects on fertility have not been performed using the fixed-combination tablets containing fexofenadine hydrochloride and pseudoephedrine hydrochloride.77,88

Lactation

It is not known if fexofenadine hydrochloride is distributed into breast milk; however, pseudoephedrine hydrochloride distributes into breast milk.77,88 Since there are no adequate and controlled studies to date on the use of fexofenadine during lactation in humans and because many drugs are excreted in human milk, the manufacturer states that fexofenadine alone or in fixed combination with pseudoephedrine hydrochloride should be used with caution in nursing women,1,77,88 and a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.77,88

Drugs Affecting Hepatic Microsomal Enzymes

The increased safety profile of fexofenadine compared with the parent drug terfenadine (no longer commercially available in the US) appears to result from the lack of cardiotoxicity in addition to minimal metabolism of fexofenadine in the liver by the cytochrome P-450 (CYP) microsomal enzyme system.1,2,8 Evidence from animal models using fexofenadine has suggested that the lack of cardiotoxic effects of the drug may result at least in part from lack of blockade of the potassium channel involved in repolarization of cardiac cells (i.e., blockade of the delayed rectifier potassium current I_K).1,8

Anti-infective Agents

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.1,77,79,88 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.1,77,88 However, no clinically important adverse effects or changes in the QT interval corrected for rate (QT_c) were reported after concomitant administration of erythromycin or ketoconazole with fexofenadine.1,2,77,79,83,88 Increases in fexofenadine plasma concentrations observed during the drug interaction studies were within the range of plasma fexofenadine concentrations achieved with fexofenadine alone in clinical trials.1,70 77,88

Data from in vitro, in situ, and in vivo studies in animals indicate that erythromycin and ketoconazole enhance absorption of concomitantly administered fexofenadine,1,77,88 possibly by affecting mechanisms of transport systems such as p-glycoprotein.77,88 In vivo animal studies suggest that, in addition to enhancing fexofenadine absorption, ketoconazole decreases fexofenadine GI secretion, while erythromycin also may decrease biliary excretion.1,77,88

Fexofenadine did not alter the pharmacokinetics of erythromycin or ketoconazole.1 No statistically significant increases in mean QT_c interval have been reported in healthy adults or patients with seasonal allergic rhinitis receiving fexofenadine hydrochloride dosages up to 400 mg twice daily (for 6 days) or 60-240 mg twice daily (for 2 weeks), respectively, in several controlled clinical studies.1,2,77,88

Antacids

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. 1 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.1,77,88

Fruit Juices

Fruit (grapefruit, orange, apple) juices may reduce bioavailability and systemic exposure of fexofenadine.77,88 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.77,88 The clinical importance of these observations is unknown.77,88 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%.77,88 Therefore, to maximize the effects of fexofenadine, the manufacturer recommends that the drug be administered with water.77,88

Pseudoephedrine

When fexofenadine hydrochloride is used concomitantly with pseudoephedrine hydrochloride, the pharmacokinetics of either drug are not altered.77,88

Monoamine Oxidase Inhibitors

Because monoamine oxidase (MAO) inhibitors potentiate the pressor effects of sympathomimetic drugs (e.g., pseudoephedrine), fixed-combination extended-release tablets containing fexofenadine hydrochloride and pseudoephedrine hydrochloride are contraindicated in patients receiving an MAO inhibitor, or for 2 weeks after discontinuance of an MAO inhibitor.77,88 For further information about drug interactions with pseudoephedrine, see Pseudoephedrine Hydrochloride 12:12.12.

Laboratory Test Interferences

Although the effect of fexofenadine on antigen skin-testing procedures has not been fully elucidated,73,74 based on the effect of terfenadine (no longer commercially available in the US) on intradermal histamine-induced whealing and pending further accumulation of data,5,72,73 the manufacturer suggests that the antihistamine be discontinued at least 24-48 hours prior to performing these tests.5,73

Acute Toxicity

Pathogenesis and Manifestation

Limited information is available on the acute toxicity of fexofenadine in humans; however, dizziness, drowsiness, and dry mouth have been reported.1,77,88 Single fexofenadine hydrochloride doses up to 800 mg and fexofenadine hydrochloride dosages of 690 mg twice daily for 1 month or fexofenadine hydrochloride dosages of 240 mg once daily for 1 year have been well tolerated in adults.1,77,88 The median lethal dose in newborn rats was 438 mg/kg (20-30 times the maximum recommended human daily dose on a mg/m² basis).77,88 No clinical signs of toxicity, gross pathologic findings, or fatalities have been reported in mice and rats receiving oral fexofenadine hydrochloride doses up to 5 g/kg (110-170 and 230-340 times the maximum recommended daily oral dosage in adults, respectively, or 200 and 400 times the maximum recommended daily oral dosage in children, respectively, based on body surface area).1,77,88 In addition, no evidence of toxicity was observed in dogs receiving oral fexofenadine hydrochloride doses up to 2 g/kg (300-450 times the maximum recommended daily oral dosage in adults or 530 times the maximum recommended daily oral dosage in children, based on body surface area).1

Treatment

For the treatment of fexofenadine overdosage, usual measures to remove unabsorbed drug from the GI tract, and supportive and symptomatic treatment should be initiated.1,77,88 Experience with terfenadine (no longer commercially available in the US), the parent drug, indicates that fexofenadine is not effectively removed by hemodialysis.1,77,88 Management of overdosage with the fixed combination of fexofenadine hydrochloride and pseudoephedrine hydrochloride should also include measures for the management of pseudoephedrine overdosage.77,88

Pharmacology

Fexofenadine is a specific, selective, histamine H₁-receptor antagonist.1,2,3,18,19,20,22,77,80,88 The pharmacology of fexofenadine resembles that of other currently available antihistamines; however, the overall pharmacologic profile of fexofenadine, like that of terfenadine (no longer commercially available in the US), differs from that of these other drugs.1,3,18,19,20,21,22 Fexofenadine is the active carboxylic acid metabolite of terfenadine,1,2,3,18,65,79 and some of the available information on the pharmacologic activity of this metabolite is derived from studies in which the parent drug terfenadine and not fexofenadine was employed.70 Although the pharmacologic activity of fexofenadine generally is thought to mimic that of the parent drug, some differences in pharmacologic actions between the parent drug and fexofenadine do exist (e.g., cardiotoxic potential).15,16,17,36,66,67

Fexofenadine has been shown to inhibit histamine release from peritoneal mast cells in rats.1,77,79,80,88 Unlike terfenadine, fexofenadine does not block the potassium channel involved in repolarization of cardiac cells (i.e., blockade of the delayed rectifier potassium current I_K).1,8,16,36,66,67,80 As a result, fexofenadine lacks the cardiotoxic potential of terfenadine.15,16,17,36,66,67,80 Fexofenadine also does not possess appreciable anticholinergic,1,2,77,80,88 antidopaminergic,2 or α- or β-adrenergic blocking1,77,88 effects at usual antihistaminic doses in pharmacologic studies.

Unlike most other currently available antihistamines (e.g., chlorpheniramine, diphenhydramine, pyribenzamine)3,20,22 but like cyproheptadine,75 terfenadine, the parent drug of fexofenadine, appears to have a dual effect on histamine H₁-receptors. In vitro studies indicate that terfenadine competitively antagonizes the actions of histamine at concentrations of about 15-47 ng/mL, while a relatively irreversible antagonism occurs at higher concentrations (i.e., 150-470 ng/mL).3,18,20,22,23 Experimental evidence indicates that terfenadine exhibits a specific and selective antagonism of histamine H₁-receptors and that the drug slowly binds to the H₁-receptor and forms a stable complex from which it subsequently slowly dissociates.2,3,18,20,23 These findings suggest that the prolonged and generally irreversible nature of terfenadine's antagonism of histamine results principally from the drug's slow dissociation from the H₁-receptors.18,20,23

In vitro, terfenadine exhibits a similar affinity for histamine H₁-receptors from brain and peripheral tissues;3,18,23,24,25,26 however, in vivo, unlike first generation antihistamines, terfenadine and fexofenadine do not readily cross the blood-brain barrier and therefore do not appear to interact appreciably with H₁-receptors within the CNS at usual doses.1,3,77,79,81,88 In animals, high doses (i.e., up to 1 g/kg orally or 100 mg/kg intraperitoneally) of terfenadine did not appear to cause appreciable CNS effects.22 The incidence of CNS effects (e.g., sedation, EEG disturbances, impaired psychomotor performance) associated with fexofenadine in clinical studies is similar to that with placebo and less than that with first generation antihistamines (e.g., chlorpheniramine, clemastine, diphenhydramine, triprolidine).1,70 (See Cautions: Nervous System Effects.) At therapeutic dosages, terfenadine generally has little, if any, clinically important effect on the EEG, sleep time, sleep latency, or rapid eye movement (REM) sleep.18,61,62,63,64

Pharmacokinetics

The pharmacokinetics of fexofenadine hydrochloride in patients with seasonal allergic rhinitis and chronic idiopathic urticaria are similar to those in healthy individuals.1,2 In addition, the pharmacokinetics of the drug in patients with hepatic impairment are similar to those observed in healthy individuals.1 No clinically important gender-related differences were observed in the pharmacokinetics of fexofenadine.1

Absorption

Fexofenadine hydrochloride is rapidly absorbed from the GI tract following oral administration.1,2,38,77,81 Following oral administration of two 60-mg fexofenadine hydrochloride capsules, peak plasma concentrations are achieved in about 2.6 hours.1,2 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.1 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.36 In healthy individuals, steady-state peak plasma concentrations averaged 286 ng/mL following administration of 60 mg of fexofenadine hydrochloride oral solution every 12 hours for 10 doses.79 Following multiple-dose administration of fexofenadine 20, 60, 120, or 240 mg twice daily to healthy individuals, the steady-state peak plasma concentration and area under the plasma-concentration time curve (AUC) of the drug were proportional to the dosage administered.79

The manufacturer states that the capsule formulation of fexofenadine hydrochloride is bioequivalent to the conventional tablet formulation of the drug.1

Following oral administration of a single 60-mg dose of fexofenadine hydrochloride (given in fixed combination with 120 mg of pseudoephedrine hydrochloride), mean peak plasma fexofenadine concentrations of 191 ng/mL are reached within 2 hours; following multiple-dose administration, steady-state, peak plasma fexofenadine concentrations of 255 ng/mL are reached within 2 hours after a dose.77 Following single- or multiple-dose administration of the fixed-combination preparation containing 180 mg of fexofenadine hydrochloride and 240 mg of pseudoephedrine hydrochloride, mean peak plasma fexofenadine concentrations of 634 or 674 ng/mL, respectively, are achieved within 1.8-2 hours after administration.88

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.38 Following oral administration of a 60-mg dose of fexofenadine hydrochloride, the AUC was 56% greater in children 7-12 years of age with allergic rhinitis than in healthy adults.1 Plasma exposure in children receiving 30 mg of fexofenadine hydrochloride is similar to that of adults receiving 60 mg of the drug.1 Limited data indicate that peak plasma fexofenadine concentrations in adolescents (12-16 years of age) were similar to those in adults, while peak plasma concentrations in geriatric adults (65 years of age and older) were 99% greater than in healthy individuals younger than 65 years of age.1,2,36,77,79,88 AUC also was higher in geriatric adults (65-80 years of age) than in younger adults (19-45 years of age); however, these values were considered to be within accepted limits.79 In addition, peak plasma concentrations of fexofenadine were 87 and 111% higher in patients with mild (creatinine clearance of 41-80 mL/minute) to severe (creatinine clearance of 11-40 mL/minute) renal impairment, respectively, compared with those observed in healthy adults.1,2,79 In patients undergoing dialysis (creatinine clearance of 10 mL/minute or less), peak plasma concentrations of fexofenadine were 82% higher than in healthy adults.1 Pharmacokinetics of fexofenadine appear to be linear for oral dosages up to 120 mg twice daily.1

Concomitant oral administration of fexofenadine hydrochloride with pseudoephedrine hydrochloride has little, if any, effect on the bioavailability of either drug.77,88 The commercially available fixed combinations containing the drugs reportedly are bioequivalent to concurrent oral administration of the drugs as individual preparations.77,88

Food may decrease peak plasma concentrations of fexofenadine hydrochloride capsules by 17%;70 however, time to achieve peak plasma concentrations of the drug does not appear to be affected.36 Furthermore, the pharmacokinetics of fexofenadine were not substantially altered when the contents of the 60-mg capsule were mixed with applesauce prior to administration.1 Therefore, the manufacturer states that fexofenadine hydrochloride capsules may be given without regard to meals.8 Absorption and peak plasma concentrations of fexofenadine are decreased when the drug is administered within 15 minutes of an antacid containing aluminum and magnesium hydroxides.1 Administration of 120 mg (two 60-mg capsules) of fexofenadine hydrochloride within 15 minutes of administration of an aluminum and magnesium hydroxides antacid (Maalox^®) resulted in 41 and 43% decreases of AUC and peak plasma concentrations of fexofenadine, respectively.1 The manufacturer states that fexofenadine hydrochloride should not be taken closely in time with antacids containing magnesium and aluminum.1,77,88

Administration of the extended-release tablets of fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride concomitantly with food appears to substantially affect the rate and/or extent of absorption of fexofenadine hydrochloride.77 88 When the fixed-combination preparation containing 60 mg of fexofenadine hydrochloride and 120 mg of pseudoephedrine hydrochloride was administered with a high-fat meal, peak plasma concentrations and AUC of fexofenadine decreased by 46 and 42%, respectively, while time to reach peak plasma concentrations of fexofenadine was delayed by 50%.77 When the fixed-combination preparation containing 180 mg of fexofenadine hydrochloride and 240 mg of pseudoephedrine hydrochloride was administered 30 minutes or 1.5 hours after a high-fat meal, peak plasma concentrations and AUC of fexofenadine decreased by 54 and 42%, respectively.88 Fruit (grapefruit, orange, apple) juices also may reduce bioavailability and systemic exposure of fexofenadine.77,88 (See Drug Interactions: Fruit Juices.) Food did not appear to affect the rate or extent of absorption of pseudoephedrine following administration of the fixed-combination preparations.77,88 Therefore, the manufacturer states that the extended-release tablets of fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride should be administered on an empty stomach with water.77,88

Following oral administration of fexofenadine hydrochloride 60-mg capsules or extended-release tablets of the drug in fixed combination with pseudoephedrine hydrochloride in a limited number of patients with seasonal allergic rhinitis, the onset of antihistaminic action occurs within 1-3 hours.1 Following oral administration of single and twice-daily doses of 20 and 40 mg of fexofenadine hydrochloride in healthy individuals, the antihistaminic effect of the drug (as determined by suppression of the wheal and flare responses induced by intradermal administration of histamine) is apparent within 1 hour, maximal within 2-3 hours, and persists for about 12 hours.1,41,77,79,81,88 Antihistaminic effect (as determined by suppression of the wheal and flare responses induced by allergens) of the drug may persist for up to 2 days in ragweed-sensitive patients receiving twice-daily doses of 60 mg of fexofenadine hydrochloride.70,79 There was no evidence of tolerance to these effects (tachyphylaxis) after 28 days of therapy;1,2,77,88 however, the clinical importance of this finding is not known.77,88 Following oral administration of a single 30- or 60-mg dose of fexofenadine in children (mean age: 7-12 years), the antihistaminic effect (as determined by suppression of the wheal and flare responses induced by intradermal administration of histamine) is apparent within 1-2 hours, maximal within 3 hours, and greater than 49 and 74% inhibition of wheal and flare area, respectively, were maintained for 8 hours;1,38 the antihistaminic effect may persist up to 24 hours, depending on the dose of the drug administered and the concentration of histamine used.38 Following oral administration of 60 mg of fexofenadine hydrochloride in patients with seasonal allergic rhinitis who were exposed to ragweed pollen, symptomatic relief of allergic reactions (excluding nasal congestion) was evident within 60 minutes and was maintained for about 12 hours.1,2,36,40,41

Distribution

Distribution of fexofenadine into human body tissues and fluids has not been fully elucidated.2 Following oral administration of fexofenadine hydrochloride in animals, the drug is distributed into the small and large intestines, stomach, pancreas, liver, and kidney.2 Fexofenadine distributes more extensively into plasma than into blood or saliva.2 The drug does not appear to cross the blood-brain barrier.1,2,77,79,81,88 It is not known if fexofenadine crosses the placenta or is distributed into breast milk.2 Fexofenadine is 60-70% bound to plasma proteins, principally albumin and α₁-acid glycoprotein.1,2,77,88 Following oral administration of single 30- or 60-mg doses of fexofenadine hydrochloride as capsules in fasting children (mean age: 8-11.6 years), the apparent volume of distribution was about 5.4 or 5.8 L/kg, respectively.38

Elimination

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.1,2,77,88 In addition, 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.38 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.1,2,77,79,88 In patients undergoing dialysis (creatinine clearance of 10 mL/minute or less), elimination half-life was 31% longer than in healthy individuals.1,77,88 About 5% of a single oral dose of fexofenadine is metabolized.1,77,88

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.70 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.70 Limited data indicate that oral clearance of the drug is 33% lower in females than in males,36,79,87 although renal clearance of the drug appears to be similar in both genders.79 In addition, oral clearance in geriatric adults (65-80 years of age) was lower than in younger adults (19-45 years of age).79,86 Following oral administration of a 30- or 60-mg dose of fexofenadine hydrochloride capsules in fasting children (mean age: 8-11.6 years), clearance rates averaged about 14.4 or 18.4 mL/minute per kg, respectively.38

Fexofenadine is eliminated principally in feces;1,2,77,78,88 however, because the absolute bioavailability of fexofenadine hydrochloride has not been established, it remains to be established whether fecal component represents unabsorbed drug or it is the result of biliary excretion.1,77,88 The drug also is excreted in urine,1,2,65,77,79,81,88 and approximately 80 and 11-12% of the drug is excreted in feces and urine, respectively.1,2,77,79,81,88

Chemistry and Stability

Chemistry

Fexofenadine is a butyrophenone-derivative antihistamine.1,2 The drug is the active carboxylic acid metabolite of terfenadine (no longer commercially available in the US) (i.e., terfenadine carboxylate),1,2,3,18,79,80 and unchanged terfenadine, not fexofenadine, is thought to be principally responsible for the cardiotoxic potential of terfenadine.15,16,17,36,66,67 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes, in the Antihistamines General Statement 4:00.) Because distribution of fexofenadine into the CNS is limited with a resultant decreased potential for adverse CNS effects compared with prototypical antihistamines, fexofenadine has been referred to as a relatively “nonsedating” or second generation antihistamine.1,2,8,79,81

Fexofenadine hydrochloride occurs as a white to off-white crystalline powder and is slightly soluble in water,1,2,77,88 having an aqueous solubility of 2.2 mg/mL at 25°C.70 The drug is freely soluble in alcohol,1,2 having a solubility of more than 300 mg/mL at 25°C.70 The pK_a(s) of the drug are 4.25 and 9.53 at 25°C.70 Fexofenadine hydrochloride occurs as a racemic mixture and exists as a zwitterion in aqueous media at physiologic pH.1,2,77,88 Both enantiomers ( R [+] and S [-]) have approximately equal antihistaminic activity.1

Allegra-D^® 12 Hour and Allegra-D^® 24 Hour tablets contain 60 or 180 mg of fexofenadine hydrochloride, respectively, in an immediate-release layer and 120 or 240 mg of pseudoephedrine hydrochloride, respectively, in an extended-release matrix layer that slowly releases the drug.70,77,88

Stability

Fexofenadine hydrochloride capsules, conventional tablets, and the extended-release tablets containing fexofenadine hydrochloride in fixed combination with pseudoephedrine hydrochloride should be stored at controlled room temperature between 20-25°C;1,77,88 foil-backed blister packages containing the drug should be protected from excessive moisture.1,2

Commercially available fexofenadine hydrochloride capsules have an expiration date of 18 or 24 months after the date of manufacture when packaged in the manufacturer's unopened blister packages or high-density polyethylene bottles, respectively.70 Commercially available fexofenadine hydrochloride 30-mg conventional tablets have an expiration date of 18 months after the date of manufacture when packaged either in the manufacturer's unopened blister packages or high-density polyethylene bottles, whereas the commercially available fexofenadine hydrochloride 60-mg conventional tablets have an expiration date of 30 months after the date of manufacture when packaged either in the manufacturer's unopened blister packages or high-density polyethylene bottles.8 In addition, fexofenadine hydrochloride 180-mg conventional tablets have an expiration date of 18 or 30 months after the date of manufacture when packaged either in the manufacturer's unopened blister packages or high-density polyethylene bottles, respectively.8

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Aventis. Allegra^® (fexofenadine hydrochloride) capsules and tablets prescribing information. Kansas City, MO; 2003 May.

2. Hoechst Marion Roussel, Inc. Product information form for American hospital formulary service: Allegra^® (fexofenadine HCl). Kansas City, MO; 1996.

3. Sorkin EM, Heel RC. Terfenadine: a review of its pharmacodynamic properties and therapeutic efficacy. Drugs . 1985; 29:34-56. [PubMed 2857636]

4. Borge PA. Problems in allergic rhinitis. Arzneimittelforschung . 1982; 32:1199-201. [PubMed 6891258]

5. Buckley CE, Klemawesch SJ, Lucas SK. Treatment of allergic rhinitis with a new selective H₁ antihistamine: terfenadine. N Engl J Med . 1985; 6:63-70.

6. Food and Drug Administration. Over-the-counter drugs: establishment of a monograph for OTC cold, cough, allergy, bronchodilator and antihistaminic products. [21 CFR 341]. Fed Regist . 1976; 41:38312-424.

7. Babe KS Jr, Serafin WE. Histamine, bradykinin and their antagonists. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996:581-600.

8. Hoechst Marion Roussel, Kansas City, MO: Personal communication.

9. Marion Merrell Dow, Kansas City, MO: Personal communication on terfenadine.

10. Honig PK, Woosley RL, Zamani K et al. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther . 1992; 52:231-8. [PubMed 1526078]

11. Woosley RL, Chen Y, Freiman JP et al. Mechanism of the cardiotoxic actions of terfenadine. JAMA . 1993; 269:1532-6. [PubMed 8445816]

12. Peck CC, Temple R, Collins JM. Understanding consequences of concurrent therapies. JAMA . 1993; 269:1550-2. [PubMed 8445821]

13. Pohjola-Sintonen S, Viitasalo M, Toivonen L et al. Torsades de pointes after terfenadine-itraconazole interaction. BMJ . 1993; 306:186.

14. Antihistamines, nonsedating/azole antifungal agents. In: Tatro DS, Olin BR, Hebel SK, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1997(October):109b.

15. Antihistamines, nonsedating/macrolide antibiotics. In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1997 (Oct):110d.

16. Food and Drug Administration. Hoechst Marion Roussel, Inc, and Baker Norton Pharmaceuticals, Inc; terfenadine; proposal to withdraw approval of two new drug applications and one abbreviated new drug application; opportunity for a hearing. [Docket No.96N-0512] Fed Regist . 1997; 62:1889-92.

17. Cruzan S. FDA proposes to withdraw Seldane approval. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 1997 Jan 13.

18. Merrell Dow Pharmaceuticals Inc. Seldane^® (terfenadine) monograph. Cincinnati, OH; 1985.

19. Merrell Dow Pharmaceuticals Inc. Product information form for American hospital formulary service on Seldane^®. Cincinnati, OH; 1985 Apr 1.

20. Cheng HC, Woodward JK. A kinetic study of the antihistaminic effect of terfenadine. Arzneimittelforschung . 1982; 32:1160-6. [PubMed 6129862]

21. Koch H. Terfenadine: specific peripheral H₁-histamine receptor antagonist. Pharm Int . 1983; 4:252-3.

22. Cheng HC, Woodward JK. Antihistaminic effect of terfenadine: a new piperidine-type antihistamine. Drug Dev Res . 1982; 2:181-96.

23. Wiech NL, Martin JS. Absence of an effect of terfenadine on guinea pig brain histamine H₁-receptors in vivo determined by receptor binding techniques. Arzneimittelforschung . 1982; 32:1167-70. [PubMed 6817763]

24. Rose C, Quach TT, Llorens C et al. Relationship between occupation of cerebral H₁-receptors and sedative properties of antihistamines: assessment in the case of terfenadine. Arzneimittelforschung . 1982; 32:1171-3. [PubMed 6129863]

25. Nicholson AN. Antihistamines and sedation. Lancet . 1983; 2:211-2. [PubMed 6135040]

26. Norman PS. New developments in treating allergic rhinitis. Drug Ther . 1984; 14:117,126,127,130-2.

27. Hoechst Marion Roussel. Seldane^® (terfenadine) tablets prescribing information. Kansas City, MO; 1997 Sep.

28. Anon. Treatment of seasonal and perennial rhinitis. \it/Br Med J\otf/. 1981; 283:808-10. (IDIS 138581)

29. Douglas WW. Histamine and 5-hydroxytryptamine (serotonin)and their antagonists. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:605-38.

30. Cirillo VJ, Tempero KF. The pharmacology and therapeutic use of H₁ and H₂ antihistamines. In: Miller RR, Greenblatt DJ, eds. Drug therapy reviews. Vol 2. New York: Elsevier/North Holland Inc; 1979:24-47.

31. Church JA. Allergic rhinitis: diagnosis and management. Clin Pediatr (Philadelphia) . 1980; 19:655-9.

32. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; tentative final monograph for OTC antihistamine drug products. [21 CFR Part 341] Fed Regist . 1985; 50:2200-18. (IDIS 195256)

33. AMA Division of Drugs. AMA drug evaluations. 5th ed. Chicago: American Medical Association; 1983:1465-79.

34. Bernstein D, Schoenwetter W, Nathan R et al. Fexofenadine: a new nonsedating antihistamine is effective in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol . 1996; 97:435.

35. Holgate S. Comparative trial of two non-sedative H₁antihistamines, terfenadine and astemizole, for hay fever. Thorax . 1985; 40:399. [PubMedCentral]

36. Anon. Fexofenadine hydrochloride: terfenadine carboxylate hydrochloride MDL- 16455A Allegra^®. Drugs Future . 1996; 21:1017-21.

37. Nightingale SL. From the Food and Drug Administration: FDA proposes to withdraw terfenadine approval. JAMA . 1997; 277:370. [PubMed 9010159]

38. Simons FER, Bergman JN, Watson WTA et al. Allergens, IgE, mediators, inflammatory mechanisms: the clinical pharmacology of fexofenadine in children. J Allergy Clin Immunol . 1996; 98:1062-4. [PubMed 8977506]

39. Anon. Fexofenadine. Med Lett Drugs Ther . 1996; 38:95-6. [PubMed 8906132]

40. Day JH, Briscoe MP, Welsh A et al. Onset of action, efficacy and safety of a single dose of 60 mg and 120 mg fexofenadine HCl for ragweed (RW) allergy using controlled antigen exposure in an enviromental exposure unit (EEU). J Allergy Clin Immunol . 1996; 97:434.

41. Tinkelman D, Falliers C, Bronsky E et al. Efficacy and safety of fexofenadine HCl in fall seasonal allergic rhinitis. J Allergy Clin Immunol . 1996; 97:435.

43. Crutcher JE, Kantner TR. The effectiveness of antihistamines in the common cold. J Clin Pharmacol . 1981; 21:9-15. [PubMed 7012191]

44. West S, Brandon B, Stolley P et al. A review of antihistamines and the common cold. Pediatrics . 1975; 56:100-7. [PubMed 240145]

45. Howard JC Jr, Kantner TR, Lilienfield LS et al. Effectiveness of antihistamines in the symptomatic management of the common cold. JAMA . 1979; 242:2414-7. [PubMed 490852]

46. Food and Drug Administration. Over-the-counter drugs: establishment of a monograph for OTC cold, cough, allergy, bronchodilator and antiasthmatic products. [DES No. 11935] Fed Regist . 1983; 48:56854-6.

47. Bryant BG, Cormier JF. Cold and allergy products. In: American Pharmaceutical Association. Handbook of nonprescription drugs. 8th ed. Washington, DC: American Pharmaceutical Association; 1986:127-74.

48. Gaffey MJ, Gwaltney JM Jr, Sastre A et al. Intranasally and orally administered antihistamine treatment of experimental rhinovirus colds. Am Rev Respir Dis . 1987; 136:556-60. [PubMed 3307567]

49. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; final monograph for OTC antihistamine drug products. Final rule. 21 CFR Parts 201, 310, 341, and 369. Fed Regist . 1992; 57:58356-8.

50. Simons FER, Simons KJ. The pharmacology and use of H₁-receptor-antagonist drugs. N Engl J Med . 1994; 330:1663-70. [PubMed 7909915]

51. Burroughs Wellcome Co. Semprex^®-D (acrivastine and pseudoephedrine HCl) capsules. Research Triangle Park, NC; 1994 Apr.

52. Douglass JA, Dhami D, Gurr CE et al. Influence of interleukin-8 challenge in the nasal mucosa in atopic and nonatopic subjects. Am J Respir Crit Care Med . 1994; 150:1108-13. [PubMed 7921444]

53. Turner RB, Sperber SJ, Sorrentino JV et al. Effectiveness of clemastine fumarate for treatment of rhinorrhea and sneezing associated with the common cold. Clin Infect Dis . 1997; 25:824-30. [PubMed 9356796]

54. Doyle WJ, McBride TP, Skoner DP et al. A double-blind, placebo-controlled clinical trial of the effect of chlorpheniramine on the response of the nasal airway, middle ear and eustachian tube to provocative rhinovirus challenge. Pediatr Infect Dis J . 1988; 7:229-38. [PubMed 3282216]

55. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; tentative final monograph for combination drug products. [21 FR Part 341] Fed Regist . 1988; 53:30522-64.

56. Turner RB. Elaboration of intereleukin 8 from fibroblast cells and human nasal epithelium in response to rhinovirus challenge. Proceedings of ICAAC Orlando 1994. Abstract No. B43.

57. Berkowitz RB, Tinkelman DG. Evaluation of terfenadine for treatment of the common cold. Ann Allergy . 1991; 67:593-7. [PubMed 1750722]

58. Gaffey MJ, Kaiser DL, Hayden FG. Ineffectiveness of oral terfenadine in natural colds: evidence against histamine as a mediator of common cold symptoms. Pediatr Infect Dis J . 1988; 7:223-8. [PubMed 2895909]

59. Proud D, Naclerio RM, Gwaltney JM et al. Kinins are generated in nasal secretions during natural rhinovirus colds. J Infect Dis . 1990; 161:120-3. [PubMed 2295843]

60. Proud D, Gwaltney JM Jr., Hendley JO et al. Increased levels of interleukin-1 are detected in nasal secretions of volunteers during experimental rhinovirus colds. J Infect Dis . 1994; 169:1007-13. [PubMed 8169385]

61. Woodward JK, Munro NL. Terfenadine, the first non-sedating antihistamine. Arzneimittelforschung . 1982; 32:1154-6. [PubMed 6129860]

62. Fink M, Irwin P. CNS effects of the antihistamines diphenhydramine and terfenadine (RMI 9918). Pharmakopsychiatr Neuro Psychopharmakol . 1979; 12:35-44.

63. Lundberg PK. Assessment of drugs' side effects: visual analogue scale versus checklist format. Percept Mot Skills . 1980; 50:1067-73. [PubMed 6774312]

64. Roehrs TA, Tietz EI, Zorick FJ et al. Daytime sleepiness and antihistamines. Sleep . 1984; 7:137-41. [PubMed 6146180]

65. Garteiz DA, Hook RH, Walker BJ et al. Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneimittelforschung . 1982; 32:1185-90. [PubMed 6817765]

66. Hey JA, del Prado M, Sherwood J et al. Comparative analysis of cardiotoxicity proclivities of second generation antihistamines in an experimental model predictive of adverse clinical ECG effects. Arneim-Forsch . 1996; 46:153-8.

67. Rampe D, Wible B, Brown AM et al. Effects of terfenadine and its metabolites on a delayed rectifier K⁺ channel cloned from human heart. Mol Pharmacol . 1993; 44:1240-5. [PubMed 8264561]

68. Smith MBH, Feldman W. Over-the-counter cold medications: a critical review of clinical trials between 1950 and 1991. JAMA . 1993; 269: 2258-63. [PubMed 8097268]

69. D Agostino RB, Weintraub M. Meta-analysis: a method for synthesizing research. Clin Pharmacol Ther . 1995; 58:605-16. [PubMed 8529325]

70. Hoechst Marion Roussel, Kansas City, MO: Personal communication.

71. Nsouli SM. Treatment of allergic rhinitis fexofenadine (FF) versus loratadine (LR). Presented at the meeting of the American College of Allergy, Asthma and Immunology. San Diego, CA: 1997 November 7-12. Abstract.

72. Hüther KJ, Renftle G, Barraud N et al. Inhibitory activity of terfenadine on histamine-induced skin wheals in man. Eur J Clin Pharmacol . 1977; 12:195-99. [PubMed 22436]

73. Merrell Dow, Cincinnati, OH: Personal communication.

74. Bateman DN, Woodhouse KW, Rawlins MD. Adverse reactions to N -acetylcysteine. Hum Toxicol . 1984; 3:393-8. [PubMed 6436169]

75. Fleischer Kupec I. FDA approves Allegra D^®, manufacturer to withdraw Seldane^® from marketplace. FDA Talk Paper . Rockville, MD: Food and Drug Administration; 1997 Dec 29.

76. Anon. Allergy drug to be pulled off U.S. shelves. Wall St J . 1997, Dec 30.

77. Aventis. Allegra-D^® 12 Hour (fexofenadine hydrochloride 60 mg and pseudoephedrine hydrochloride 120 mg) extended-release tablets prescribing information. Kansas City, MO; 2004 Dec.

78. Pinto YM, van Gelder IC, Heeringa M et al. QT lengthening and life-threatening arrhythmias associated with fexofenadine. Lancet . 1999; 353:980. [PubMed 10459910]

79. Markham A, Wagstaff AJ. Comment on fexofenadine. Drugs . 1998; 55:269-74. [PubMed 9506246]

80. Galant SP. Comments on fexofenadine. Drugs . 1998; 55:275.

81. Simons FER. Comments on fexofenadine. Drugs . 1998; 55:275-6.

82. Sussman GL, Mason J, Compton D et al. The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone and in combination, in seasonal allergic rhinitis. J Allergy Clin Immunol . 1999; 104:100-6. [PubMed 10400846]

83. Pratt CM, Mason J, Russell T et al. Cardiovascular safety of fexofenadine HCl. Am J Cardiol . 1999; 83:1451-1454. [PubMed 10335761]

84. Giraud T. QT lengthening and arrhythmias associated with fexofenadine. Lancet . 1999; 353:2072. [PubMed 10376646]

85. Pinto YM, van Gelder IC, Heeringa M at al. QT lengthening and arrhythmias associated with fexofenadine. Lancet . 1999; 353:2072-3. [PubMed 10376646]

86. Rao N, Weilert DR, Grace MGA et al. Pharmacokinetics of terfenadine-acid metabolite, MDL 16,455, in healthy geriatric subjects. Pharm Res . 1995 12 (Suppl 9):S-386. Abstract No. PPDM 8240.

87. Russell T, Arumugham T, Eller M et al. A comparison of MDL 16,455A pharmacokinetics by gender. Pharm Res . 1995 12 (Suppl 9): S-389. Abstract No. PPDM 8252.

88. Aventis. Allegra-D^® 24 Hour (fexofenadine hydrochloride 180 mg and pseudoephedrine hydrochloride 240 mg) extended-release tablets prescribing information. Kansas City, MO; 2005 Jan.

89. Srinivasan A, Budnitz D, Shehab N et al. Infant deaths associated with cough and cold medications—two states, 2005. MMWR Morb Mortal Wkly Rep . 2007; 56:1-4. [PubMed 17218934]

90. Food and Drug Administration. Cough and cold medications in children less than two years of age. Rockville, MD; 2007 Jan 12. From FDA website. [Web]