NONTERATOGENIC EFFECTS SECTION.


Nonteratogenic Effects. Dose-relateddecreases in pup weight gain and survival were observed in rats exposedto an oral dose of 150 mg/kg of terfenadine (approximately timesthe maximum recommended human daily oral dose of fexofenadine hydrochlorideof 180 mg in adults based on comparison of fexofenadine hydrochlorideAUCs).

NURSING MOTHERS SECTION.


NURSING MOTHERS. It is not knownif fexofenadine is excreted in human milk. There are no adequate andwell-controlled studies in women during lactation. Because many drugsare excreted in human milk, caution should be exercised when fexofenadinehydrochloride is administered to nursing woman.

ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS. Seasonal Allergic Rhinitis. Adults. In placebo-controlledseasonal allergic rhinitis clinical trials in subjects 12 years ofage and older, which included 2461 subjects receiving fexofenadinehydrochloride capsules at doses of 20 mg to 240 mg twice daily, adverseevents were similar in fexofenadine hydrochloride- and placebo-treatedsubjects. All adverse events that were reported by greater than 1%of subjects who received the recommended daily dose of fexofenadinehydrochloride (60 mg capsules twice daily), and that were more commonwith fexofenadine hydrochloride than placebo, are listed in Table1.In placebo-controlled clinical study in the United States, whichincluded 570 subjects aged 12 years and older receiving fexofenadinehydrochloride tablets at doses of 120 or 180 mg once daily, adverseevents were similar in fexofenadine hydrochloride- and placebo-treatedsubjects. Table also lists adverse experiences that were reportedby greater than 2% of subjects treated with fexofenadine hydrochloridetablets at doses of 180 mg once daily and that were more common withfexofenadine hydrochloride than placebo.The incidence of adverse events, including drowsiness, was not dose-relatedand was similar across subgroups defined by age, gender, and race. Table Adverse experiences in subjects aged 12 years and older reportedin placebo-controlled seasonal allergic rhinitis clinical trials inthe United States Twice- dailydosing with fexofenadine capsules at rates of greater than 1% Adverse experience Fexofenadine 60 mgTwice Daily(n=679) PlaceboTwice Daily(n=671) Viral Infection (cold, flu) 2.5% 1.5% Nausea 1.6% 1.5% Dysmenorrhea 1.5% 0.3% Drowsiness 1.3% 0.9% Dyspepsia 1.3% 0.6% Fatigue 1.3% 0.9% Once daily dosing with fexofenadine hydrochloridetabletsat rates of greater than 2% Adverse experience Fexofenadine 180 mgOnce Daily(n=283) Placebo(n=293) Headache 10.6% 7.5% Upper Respiratory Tract Infection 3.2% 3.1% Back Pain 2.8% 1.4%The frequencyand magnitude of laboratory abnormalities were similar in fexofenadinehydrochloride- and placebo-treated subjects.. Pediatrics. Table 2lists adverse experiences in subjects aged to 11 years of age whichwere reported by greater than 2% of subjects treated with fexofenadinehydrochloride tablets at dose of 30 mg twice daily in placebo-controlledseasonal allergic rhinitis studies in the United States and Canadathat were more common with fexofenadine hydrochloride than placebo. Table Adverse experiences reported in placebo-controlled seasonalallergic rhinitis studies in pediatric subjects aged to 11 in theUnited States and Canada at rates of greater than 2% Adverse experience Fexofenadine 30 mgTwice Daily(n=209) Placebo(n=229) Headache 7.2% 6.6% Accidental Injury 2.9% 1.3% Coughing 3.8% 1.3% Fever 2.4% 0.9% Pain 2.4% 0.4% Otitis Media 2.4% 0.0% Upper Respiratory Tract Infection 4.3% 1.7%Threeclinical safety studies in 845 children aged months to years comparing15 mg twice daily (n=85) and 30 mg twice daily (n=330) of anexperimental formulation of fexofenadine to placebo (n=430) have beenconducted. In general, fexofenadine hydrochloride was well toleratedin these studies. No unexpected adverse events were seen given theknown safety profile of fexofenadine and likely adverse reactionsfor this patient population. (See PRECAUTIONS Pediatric Use.). Chronic Idiopathic Urticaria. Adverse events reportedby subjects 12 years of age and older in placebo-controlled chronicidiopathic urticaria studies were similar to those reported in placebo-controlledseasonal allergic rhinitis studies. In placebo-controlled chronicidiopathic urticaria clinical trials, which included 726 subjects12 years of age and older receiving fexofenadine hydrochloride tabletsat doses of 20 to 240 mg twice daily, adverse events were similarin fexofenadine hydrochloride- and placebo-treated patients. Table3 lists adverse experiences in subjects aged 12 years and older whichwere reported by greater than 2% of subjects treated with fexofenadinehydrochloride 60 mg tablets twice daily in controlled clinical studiesin the United States and Canada and that were more common with fexofenadinehydrochloride than placebo. In placebo-controlled clinical study in the United States, whichincluded 167 subjects aged 12 years and older receiving fexofenadinehydrochloride 180 mg tablets, adverse events were similar in fexofenadinehydrochloride- and placebo-treated subjects. Table also lists adverseexperiences that were reported by greater than 2% of subjects treatedwith fexofenadine hydrochloride tablets at doses of 180 mg once dailyand that were more common with fexofenadine hydrochloride than placebo.The safety of fexofenadinehydrochloride in the treatment of chronic idiopathic urticaria inpediatric patients to 11 years of age is based on the safety profileof fexofenadine hydrochloride in adults and adolescent patients atdoses equal to or higher than the recommended dose (see Pediatric Use).Table Adverse experiences reported in subjects12 years of age and older in placebo-controlled chronic idiopathicurticaria studies Twice-dailydosing with fexofenadine hydrochloride in studies in the UnitedStates and Canada at rates of greater than 2% Adverse experience Fexofenadine 60 mgTwice Daily(n=191) Placebo(n=183) Dyspepsia 4.7% 4.4% Myalgia 2.6% 2.2% Back Pain 2.1% 1.1% Dizziness 2.1% 1.1% Pain in extremity 2.1% 0.0% Once-daily dosing with fexofenadine hydrochloridein study in the United States at rates of greater than 2% Adverse experience Fexofenadine 180 mg Once Daily (n=167) Placebo (n=92) Headache 4.8% 3.3% Nasopharyngitis 2.4% 2.2% Upper respiratory tract infection 2.4% 2.2%Events that havebeen reported during controlled clinical trials involving seasonalallergic rhinitis and chronic idiopathic urticaria subjects with incidencesless than 1% and similar to placebo and have been rarely reportedduring postmarketing surveillance include: insomnia, nervousness,and sleep disorders or paroniria. In rare cases, rash, urticaria,pruritus and hypersensitivity reactions with manifestations such asangioedema, chest tightness, dyspnea, flushing and systemic anaphylaxishave been reported.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY. The carcinogenicpotential and reproductive toxicity of fexofenadine hydrochloridewere assessed using terfenadine studies with adequate fexofenadinehydrochloride exposure (based on plasma area-under-the-concentrationvs. time [AUC] values). No evidence of carcinogenicity was observedin an 18-month study in mice and in 24-month study in rats at oraldoses up to 150 mg/kg of terfenadine (which led to fexofenadine exposuresthat were approximately and times the exposure from the maximumrecommended human daily oral dose of fexofenadine hydrochloride inadults [180 mg] and children [60 mg] respectively .In in vitro (Bacterial ReverseMutation, CHO/HGPRT Forward Mutation, and Rat Lymphocyte ChromosomalAberration assays) and in vivo (Mouse Bone Marrow Micronucleus assay) tests, fexofenadine hydrochloriderevealed no evidence of mutagenicity.In rat dietary fertility studies, dose-related reductions in implantsand increases in postimplantation losses were observed at an oraldose of 150 mg/kg of terfenadine (which led to fexofenadine hydrochlorideexposures that were approximately times the exposure of the maximumrecommended human daily oral dose of 180 mg fexofenadine hydrochloride).In mice, fexofenadine hydrochloride produced no effect on male orfemale fertility at average dietary doses up to 4438 mg/kg (approximately10 times the maximum recommended human daily oral dose of fexofenadinehydrochloride 180 mg based on comparison of AUCs).

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY. Mechanism of Action. Fexofenadine hydrochloride,the major active metabolite of terfenadine, is an antihistamine withselective peripheral H1-receptor antagonist activity. Bothenantiomers of fexofenadine hydrochloride displayed approximatelyequipotent antihistaminic effects. Fexofenadine hydrochloride inhibitedantigen-induced bronchospasm in sensitized guinea pigs and histaminerelease from peritoneal mast cells in rats. The clinical significanceof these findings is unknown. In laboratory animals, no anticholinergicor alpha1-adrenergic blocking effects were observed. Moreover,no sedative or other central nervous system effects were observed.Radiolabeled tissue distribution studies in rats indicated that fexofenadinedoes not cross the blood-brain barrier. Pharmacokinetics. The pharmacokineticsof fexofenadine hydrochloride in subjects with seasonal allergic rhinitisand subjects with chronic urticaria were similar to those in healthyvolunteers.. Absorption. Fexofenadinehydrochloride was rapidly absorbed following oral administration ofa single dose of two 60 mg capsules to healthy male volunteers witha mean time to maximum plasma concentration occurring at 2.6 hourspost-dose. After administration of single 60 mg capsule to healthyvolunteers, the mean maximum plasma concentration was 131 ng/mL. Followingsingle dose oral administrations of either the 60 and 180 mg tabletto healthy adult male volunteers, mean maximum plasma concentrationswere 142 and 494 ng/mL, respectively. The tablet formulations arebioequivalent to the capsule when administered at equal doses. Fexofenadinehydrochloride pharmacokinetics are linear for oral doses up to totaldaily dose of 240 mg (120 mg twice daily). The administration of the60 mg capsule contents mixed with applesauce did not have significanteffect on the pharmacokinetics of fexofenadine in adults.Co-administrationof 180 mg fexofenadine hydrochloride tablet with high fat meal decreasedthe AUC and Cmax of fexofenadine by 21 and 20% respectively. Distribution. Fexofenadinehydrochloride is 60% to 70% bound to plasma proteins, primarily albuminand 1-acid glycoprotein.. Metabolism. Approximately5% of the total dose of fexofenadine hydrochloride was eliminatedby hepatic metabolism.. Elimination. The meanelimination half-life of fexofenadine was 14.4 hours following administrationof 60mg, twice daily, in healthy volunteers.Human mass balance studies documented recovery of approximately80% and 11% of the [14C] fexofenadine hydrochloride dosein the feces and urine, respectively. Because the absolute bioavailabilityof fexofenadine hydrochloride has not been established, it is unknownif the fecal component represents primarily unabsorbed drug or theresult of biliary excretion.. Special Populations. Pharmacokineticsin special populations (for renal, hepatic impairment, and age), obtainedafter single dose of 80 mg fexofenadine hydrochloride, were comparedto those from healthy volunteers in separate study of similar design.. Geriatric Subjects. In older subjects (>=65 years old), peak plasma levels offexofenadine were 99% greater than those observed in younger subjects(<65 years old). Mean fexofenadine elimination half-lives weresimilar to those observed in younger subjects.. Pediatric Subjects. Cross study comparisons indicated that fexofenadine area under thecurve (AUC) following oral administration of 60 mg dose of fexofenadinehydrochloride to 7-12 year old pediatric subjects with allergicrhinitis was 56% greater compared to healthy adult volunteersgiven the same dose. Plasma exposure in pediatric subjects given 30mg fexofenadine hydrochloride is comparable to adults given 60 mg.. Renally Impaired. In subjects with mild to moderate (creatinine clearance 41-80mL/min) and severe (creatinine clearance 11-40 mL/min) renalimpairment, peak plasma levels of fexofenadine were 87% and 111% greater,respectively, and mean elimination half-lives were 59% and 72% longer,respectively, than observed in healthy volunteers. Peak plasma levelsin subjects on dialysis (creatinine clearance <=10 mL/min) were82% greater and half-life was 31% longer than observed in healthyvolunteers. Based on increases in bioavailability and half-life, adose of 60 mg once daily is recommended as the starting dose in patientswith decreased renal function. (See DOSAGE AND ADMINISTRATION).. Hepatically Impaired. The pharmacokinetics of fexofenadine in subjects with hepatic diseasedid not differ substantially from that observed in healthy volunteers.. Effect of Gender. Across several trials, no clinically significant gender-related differenceswere observed in the pharmacokinetics of fexofenadine hydrochloride. Pharmacodynamics. Wheal and Flare. Human histamineskin wheal and flare studies following single and twice daily dosesof 20 and 40 mg fexofenadine hydrochloride demonstrated that the drugexhibits an antihistamine effect by hour, achieves maximum effectat to hours, and an effect is still seen at 12 hours. There wasno evidence of tolerance to these effects after 28 days of dosing.The clinical significance of these observations is unknown. Histamine skinwheal and flare studies in to 12 year old subjects showed that followinga single dose of 30 or 60 mg, antihistamine effect was observed at1 hour and reached maximum by hours. Greater than 49% inhibitionof wheal area, and 74% inhibition of flare area were maintained for8 hours following the 30 and 60 mg dose.. Effects on QTc In dogs(30 mg/kg/orally twice daily for days) and rabbits (10 mg/kg, intravenously over hour), fexofenadine hydrochloride did not prolongQTc. In dogs, the plasma fexofenadine concentration wasapproximately times the therapeutic plasma concentrations in adultsreceiving the maximum recommended human daily oral dose of 180 mg.In rabbits, the plasma fexofenadine concentration was approximately20 times the therapeutic plasma concentration in adults receivingthe maximum recommended human daily oral dose of 180 mg. No effectwas observed on calcium channel current, delayed K+ channelcurrent, or action potential duration in guinea pig myocytes, Na+ current in rat neonatal myocytes, or on the delayed rectifierK+ channel cloned from human heart at concentrations upto x 10-5 of fexofenadine.No statistically significant increase in mean QTc intervalcompared to placebo was observed in 714 subjects with seasonal allergicrhinitis given fexofenadine hydrochloride capsules in doses of60 to 240 mg twice daily for weeks. Pediatric subjects from placebo-controlled trials (n=855) treated with up to 60 mg fexofenadine hydrochloridetwice daily demonstrated no significant treatment- or dose-relatedincreases in QTc. In addition, no statistically significantincrease in mean QTc interval compared to placebo was observedin 40 healthy volunteers given fexofenadine hydrochloride as an oralsolution at doses up to 400 mg twice daily for days, or in 230 healthyvolunteers given fexofenadine hydrochloride 240 mg once daily for1 year. In subjects with chronic idiopathic urticaria, there wereno clinically relevant differences for any ECG intervals, includingQTc, between those treated with fexofenadine hydrochloride180 mg once daily (n 163) and those treated with placebo (n 91)for weeks.

CLINICAL STUDIES SECTION.


CLINICAL STUDIES. Seasonal Allergic Rhinitis. Adults. In three2-week, multicenter, randomized, double-blind, placebo-controlledtrials in subjects 12 to 68 years of age with seasonal allergic rhinitis(n=1634), fexofenadine hydrochloride 60 mg twice daily significantlyreduced total symptom scores (the sum of the individual scores forsneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes)compared to placebo. Statistically significant reductions in symptomscores were observed following the first 60 mg dose, with the effectmaintained throughout the 12-hour interval. In these studies, therewas no additional reduction in total symptom scores with higher dosesof fexofenadine hydrochloride up to 240 mg twice daily.In one 2-week,multicenter, randomized, double-blind clinical trial in subjects 12to 65 years of age with seasonal allergic rhinitis (n=863), fexofenadinehydrochloride 180 mg once daily significantly reduced total symptomscores (the sum of the individual scores for sneezing, rhinorrhea,itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo.Although the number of subjects in some of the subgroups was small,there were no significant differences in the effect of fexofenadinehydrochloride across subgroups of subjects defined by gender, age,and race. Onset of action for reduction in total symptom scores, excludingnasal congestion, was observed at 60 minutes compared to placebo followinga single 60 mg fexofenadine hydrochloride dose administered to subjectswith seasonal allergic rhinitis who were exposed to ragweed pollenin an environmental exposure unit. In clinical trial conducted withfexofenadine hydrochloride 60 mg capsules, and in clinical trialconducted with fexofenadine hydrochloride/pseudoephedrine hydrochlorideextended release tablets, onset of action was seen within to hours.. Pediatrics. Two 2-weekmulticenter, randomized, placebo-controlled, double-blind trials in877 pediatric subjects to 11 years of age with seasonal allergicrhinitis were conducted at doses of 15, 30, and 60 mg twice daily.In of these studies, conducted in 411 pediatric subjects, all3 doses of fexofenadine hydrochloride significantly reduced totalsymptom scores (the sum of the individual scores for sneezing, rhinorrhea,itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo,however, dose-response relationship was not seen. The 60 mg twicedaily dose did not provide any additional benefit over the 30 mg twicedaily dose. Furthermore, exposure in pediatric subjects given 30 mgfexofenadine hydrochloride is comparable to adults given 60 mg (see CLINICAL PHARMACOLOGY).Three clinicalsafety studies in 845 children aged months to years with allergicrhinitis comparing 15 mg twice daily (n=85) and 30 mg twice daily(n=330) of an experimental formulation of fexofenadine to placebo(n=430) have been conducted. Ingeneral, fexofenadine hydrochloride was well tolerated in these studies.No unexpected adverse events were seen given the known safety profileof fexofenadine and likely adverse reactions for this patient population. (See PRECAUTIONS Pediatric Use and ADVERSE REACTIONS.). Chronic Idiopathic Urticaria. Two 4-week multicenter,randomized, double-blind, placebo-controlled clinical trials comparedfour different doses of fexofenadine hydrochloride tablet (20, 60,120, and 240 mg twice daily) to placebo in subjects aged 12 to 70years with chronic idiopathic urticaria (n=726). Efficacy was demonstratedby significant reduction in mean pruritus scores (MPS), mean numberof wheals (MNW), and mean total symptom scores (MTSS, the sum of theMPS and MNW score). Although all doses were significantly superiorto placebo, symptom reduction was greater and efficacy was maintainedover the entire 4-week treatment period with fexofenadine hydrochloridedoses of >=60 mg twice daily. However, no additional benefitof the 120 or 240 mg fexofenadine hydrochloride twice daily dose wasseen over the 60 mg twice daily dose in reducing symptom scores. Therewere no significant differences in the effect of fexofenadine hydrochlorideacross subgroups of subjects defined by gender, age, weight, and race. In one 4-week, multicenter,randomized, double-blind, placebo-controlled clinical trial in subjects12 years of age and older with chronic idiopathic urticaria (n=259),fexofenadine hydrochloride 180 mg once daily significantly reducedthe mean number of wheals (MNW), the mean pruritus score (MPS), andthe mean total symptom score (MTSS, the sum of the MPS and MNW scores).Similar reductions were observed for mean number of wheals and meanpruritus score at the end of the 24-hour dosing interval. Symptomreduction was greater with fexofenadine hydrochloride 180 mg thanwith placebo. Improvement was demonstrated within day of treatmentwith fexofenadine hydrochloride 180 mg and was maintained over theentire 4-week treatment period. There were no significant differencesin the effect of fexofenadine hydrochloride across subgroups of subjectsdefined by gender, age, and race.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS. Fexofenadine HydrochlorideTablets are contraindicated in patients with known hypersensitivityto any of its ingredients.

DESCRIPTION SECTION.


DESCRIPTION. Fexofenadine hydrochloride is histamine H1-receptor antagonist with the chemical name (+-)-4-[1 hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-,-dimethyl benzeneacetic acid hydrochloride. It has the following chemical structure The molecular weight is 538.13 and the empirical formula is C32H39NO4oHCl.Fexofenadine hydrochloride is 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 racemate and exists as zwitterion in aqueous media at physiological pH.Fexofenadine hydrochloride is formulated as tablet for oral administration. Each tablet contains 30, 60, or 180 mg fexofenadine hydrochloride (depending on the dosage strength) and the following excipients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The aqueous tablet film coating is made from hypromellose, iron oxide blends, polyethylene glycol, povidone, silicone dioxide, and titanium dioxide.. Fexofenadine HCL Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION. Seasonal Allergic Rhinitis. Adults and Children 12 Years and Older. The recommendeddose of Fexofenadine Hydrochloride Tablets is 60 mg twice daily, or180 mg once daily with water. dose of 60 mg once daily is recommendedas the starting dose in patients with decreased renal function (see CLINICAL PHARMACOLOGY).. Children to 11 Years. The recommendeddose of Fexofenadine Hydrochloride Tablets is 30 mg twice daily withwater. dose of 30 mg once daily is recommended as the starting dosein pediatric patients with decreased renal function (see CLINICAL PHARMACOLOGY).. Chronic Idiopathic Urticaria. Adults and Children 12 Years and Older. The recommendeddose of Fexofenadine Hydrochloride Tablets is 60 mg twice daily or180 mg once daily with water. dose of 60 mg once daily is recommendedas the starting dose in patients with decreased renal function (see CLINICAL PHARMACOLOGY).. Children to 11 Years. The recommendeddose of Fexofenadine Hydrochloride Tablets is 30 mg twice daily withwater. dose of 30 mg once daily is recommended as the starting dosein pediatric patients with decreased renal function (see CLINICAL PHARMACOLOGY).

GERIATRIC USE SECTION.


GERIATRIC USE. Clinical studiesof fexofenadine hydrochloride tablets and capsules did not includesufficient numbers of subjects aged 65 years and over to determinewhether this population responds differently from younger subjects.Other reported clinical experience has not identified differencesin responses between the geriatric and younger subjects. This drugis known to be substantially excreted by the kidney, and the riskof toxic reactions to this drug may be greater in patients with impairedrenal function. Because elderly patients are more likely to have decreasedrenal function, care should be taken in dose selection, and it maybe useful to monitor renal function. (See CLINICAL PHARMACOLOGY).

HOW SUPPLIED SECTION.


HOW SUPPLIED. Fexofenadine Hydrochloride Tablets 60 mg are available in blisterpacks of 30 (NDC 0615-5620-39).Fexofenadine Hydrochloride Tablets 180 mg are available in blisterpacks of 30 (NDC 0615-5619-39)Fexofenadine Hydrochloride Tablets are coated with peach colored film coating. Tablets have the following unique identifiers: 30 mg tablets have 03 on one side, 60 mg tablets have 06 on one side, and 180 mg tablets have 018 on one side.Store Fexofenadine Hydrochloride Tablets at controlled room temperature 20-25C (68-77F). (See USP Controlled Room Temperature). Fexofenadine Hydrochloride Tablets should be protected from excessive moisture.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE. Seasonal Allergic Rhinitis. Fexofenadine HydrochlorideTablets are indicated for the relief of symptoms associated with seasonalallergic rhinitis in adults and children years of age and older.Symptoms treated effectively were sneezing, rhinorrhea, itchy nose/palate/throat,itchy/watery/red eyes. Chronic Idiopathic Urticaria. Fexofenadine HydrochlorideTablets are indicated for treatment of uncomplicated skin manifestationsof chronic idiopathic urticaria in adults and children years ofage and older. It significantly reduces pruritus and the number ofwheals.

INFORMATION FOR PATIENTS SECTION.


Information for Patients. Patients takingFexofenadine Hydrochloride Tablets should receive the following information:Fexofenadine HydrochlorideTablets are prescribed for the relief of symptoms of seasonal allergicrhinitis or for the relief of symptoms of chronic idiopathic urticaria(hives). Patients should be instructed to take Fexofenadine HydrochlorideTablets only as prescribed. Do not exceed the recommended dose. Ifany untoward effects occur while taking Fexofenadine HydrochlorideTablets, discontinue use and consult the doctor.The product should not be used by patients who are hypersensitiveto it or to any of its ingredients.Patients should be told that this product should be used in pregnancyor lactation only if the potential benefit justifies the potentialrisk to the fetus or nursing infant.Patients should be advised to take the tablet with water. Patientsshould also be advised to store the medication in tightly closedcontainer in cool, dry place, away from children.

OVERDOSAGE SECTION.


OVERDOSAGE. Reports of fexofenadinehydrochloride overdose have been infrequent and contain limited information.However, dizziness, drowsiness, and dry mouth have been reported.Single doses of fexofenadine hydrochloride up to 800 mg (6 healthyvolunteers at this dose level), and doses up to 690 mg twice dailyfor month (3 healthy volunteers at this dose level) or 240 mg oncedaily for year (234 healthy volunteers at this dose level) wereadministered without the development of clinically significant adverseevents as compared to placebo.In the event of overdose, consider standard measures to remove anyunabsorbed drug. Symptomatic and supportive treatment is recommended.Following administration of terfenadine, hemodialysis did not effectivelyremove fexofenadine, the major active metabolite of terfenadine, fromblood (up to 1.7% removed).No deaths occurred at oral doses of fexofenadine hydrochloride upto 5000 mg/kg in mice (110 times the maximum recommended human dailyoral dose in adults and 200 times the maximum recommended human dailyoral dose in children based on mg/m2) and up to 5000 mg/kgin rats (230 times the maximum recommended human daily oral dose inadults and 400 times the maximum recommended human daily oral dosein children based on mg/m2). Additionally, no clinicalsigns of toxicity or gross pathological findings were observed. Indogs, no evidence of toxicity was observed at oral doses up to 2000mg/kg (300 times the maximum recommended human daily oral dose inadults and 530 times the maximum recommended human daily oral dosein children based on mg/m2).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL PRINCIPAL DISPLAY PANEL. Fexofenadine Hydrochloride Tablets,60mg. Principal Display Panel-Fexofenadine HCL 60mg.

PEDIATRIC USE SECTION.


PEDIATRIC USE. The recommendeddose in patients to 11 years of age is based on cross-study comparisonof the pharmacokinetics of fexofenadine hydrochloride in adults andpediatric subjects and on the safety profile of fexofenadine hydrochloridein both adult and pediatric subjects at doses equal to or higher thanthe recommended doses.The safety of fexofenadine hydrochloride tablets at dose of 30mg twice daily has been demonstrated in 438 pediatric subjects to11 years of age in two placebo-controlled 2-week seasonal allergicrhinitis trials. The safety of fexofenadine hydrochloride for thetreatment of chronic idiopathic urticaria in subjects to 11 yearsof age is based on cross-study comparison of the pharmacokineticsof fexofenadine hydrochloride in adult and pediatric subjects andon the safety profile of fexofenadine in both adult and pediatricsubjects at doses equal to or higher than the recommended dose.The effectiveness offexofenadine hydrochloride for the treatment of seasonal allergicrhinitis in subjects to 11 years of age was demonstrated in1 trial (n=411) in which fexofenadine hydrochloride tablets 30 mgtwice daily significantly reduced total symptom scores compared toplacebo, along with extrapolation of demonstrated efficacy in subjectsaged 12 years and above, and the pharmacokinetic comparisons in adultsand children. The effectiveness of fexofenadine hydrochloride forthe treatment of chronic idiopathic urticaria in patients to 11years of age is based on an extrapolation of the demonstrated efficacyof fexofenadine hydrochloride in adults with this condition and thelikelihood that the disease course, pathophysiology and the drugseffect are substantially similar in children to that of adult patients.Three clinical safetystudies comparing 15 mg twice daily (n=85) and 30 mg twice daily (n=330)of an experimental formulation of fexofenadine to placebo (n=430)have been conducted in pediatric subjects aged months to years. Ingeneral, fexofenadine hydrochloride was well tolerated in these studies.No unexpected adverse events were seen given the known safety profileof fexofenadine and likely adverse reactions for this patient population.(See ADVERSE REACTIONS and CLINICAL PHARMACOLOGY.)The safetyand effectiveness of fexofenadine hydrochloride in pediatric patientsunder years of age have not been established.

PRECAUTIONS SECTION.


PRECAUTIONS. Information for Patients. Patients takingFexofenadine Hydrochloride Tablets should receive the following information:Fexofenadine HydrochlorideTablets are prescribed for the relief of symptoms of seasonal allergicrhinitis or for the relief of symptoms of chronic idiopathic urticaria(hives). Patients should be instructed to take Fexofenadine HydrochlorideTablets only as prescribed. Do not exceed the recommended dose. Ifany untoward effects occur while taking Fexofenadine HydrochlorideTablets, discontinue use and consult the doctor.The product should not be used by patients who are hypersensitiveto it or to any of its ingredients.Patients should be told that this product should be used in pregnancyor lactation only if the potential benefit justifies the potentialrisk to the fetus or nursing infant.Patients should be advised to take the tablet with water. Patientsshould also be advised to store the medication in tightly closedcontainer in cool, dry place, away from children. Drug Interaction with Erythromycin and Ketoconazole. Fexofenadine hasbeen shown to exhibit minimal (ca. 5%) metabolism. However, co-administrationof fexofenadine hydrochloride with either ketoconazole or erythromycinled to increased plasma concentrations of fexofenadine. Fexofenadinehad no effect on the pharmacokinetics of either erythromycin or ketoconazole.In separate studies, fexofenadine hydrochloride 120 mg twice daily(240 mg total daily dose) was co-administered with either erythromycin500 mg every hours or ketoconazole 400 mg once daily under steady-stateconditions to healthy volunteers (n=24, each study). No differencesin adverse events or QTc interval were observed when subjectswere administered fexofenadine hydrochloride alone or in combinationwith either erythromycin or ketoconazole. The findings of these studiesare summarized in the following table:Effects on steady-state fexofenadine pharmacokineticsafter days of co-administration with fexofenadine hydrochloride120 mg every 12 hours (two times the recommended twice daily dose)in healthy volunteers (n=24)Concomitant DrugCmaxSS (Peak plasma concentration)AUCss(0-12h) (Extent of systemic exposure) Erythromycin +82% +109% (500 mg every hrs) Ketoconazole +135% +164% (400 mg once daily) The changes inplasma levels were within the range of plasma levels achieved in adequateand well-controlled clinical trials.The mechanism of these interactions has been evaluated in in vitro, in situ, and in vivo animal models. These studiesindicate that ketoconazole or erythromycin co-administration enhancesfexofenadine gastrointestinal absorption. This observed increase inthe bioavailability of fexofenadine may be due to transport-relatedeffects, such as p-glycoprotein. In vivo animal studies also suggest that in addition to enhancing absorption,ketoconazole decreases fexofenadine gastrointestinal secretion, whileerythromycin may also decrease biliary excretion.. Drug Interactions with Antacids. Administration of120 mg of fexofenadine hydrochloride (2 60 mg capsule) within15 minutes of an aluminum and magnesium containing antacid (Maalox(R)) decreased fexofenadine AUC by 41% and Cmax by 43%.Fexofenadine hydrochloride should not be taken closely in time withaluminum and magnesium containing antacids.. Interactions with Fruit Juices. Fruit juices suchas grapefruit, orange and apple may reduce the bioavailability andexposure of fexofenadine. This is based on the results from clinicalstudies using histamine induced skin wheals and flares coupled withpopulation pharmacokinetic analysis. The size of wheal and flare weresignificantly larger when fexofenadine hydrochloride was administeredwith either grapefruit or orange juices compared to water. Based onthe literature reports, the same effects may be extrapolated to otherfruit juices such as apple juice. The clinical significance of theseobservations is unknown. In addition, based on the population pharmacokineticsanalysis of the combined data from grapefruit and orange juices studieswith the data from bioequivalence study, the bioavailability offexofenadine was reduced by 36%. Therefore, to maximize the effectsof fexofenadine, it is recommended that Fexofenadine hydrochlorideshould be taken with water (see Dosage and Administration).. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY. The carcinogenicpotential and reproductive toxicity of fexofenadine hydrochloridewere assessed using terfenadine studies with adequate fexofenadinehydrochloride exposure (based on plasma area-under-the-concentrationvs. time [AUC] values). No evidence of carcinogenicity was observedin an 18-month study in mice and in 24-month study in rats at oraldoses up to 150 mg/kg of terfenadine (which led to fexofenadine exposuresthat were approximately and times the exposure from the maximumrecommended human daily oral dose of fexofenadine hydrochloride inadults [180 mg] and children [60 mg] respectively .In in vitro (Bacterial ReverseMutation, CHO/HGPRT Forward Mutation, and Rat Lymphocyte ChromosomalAberration assays) and in vivo (Mouse Bone Marrow Micronucleus assay) tests, fexofenadine hydrochloriderevealed no evidence of mutagenicity.In rat dietary fertility studies, dose-related reductions in implantsand increases in postimplantation losses were observed at an oraldose of 150 mg/kg of terfenadine (which led to fexofenadine hydrochlorideexposures that were approximately times the exposure of the maximumrecommended human daily oral dose of 180 mg fexofenadine hydrochloride).In mice, fexofenadine hydrochloride produced no effect on male orfemale fertility at average dietary doses up to 4438 mg/kg (approximately10 times the maximum recommended human daily oral dose of fexofenadinehydrochloride 180 mg based on comparison of AUCs).. PREGNULLNCY. Teratogenic Effects. Category C.There was no evidence of teratogenicity in rats or rabbits at oraldoses of terfenadine up to 300 mg/kg (which led to fexofenadine exposuresthat were approximately and 30 times, respectively, the exposurefrom the maximum recommended human daily oral dose of fexofenadinehydrochloride of 180 mg based on comparison of AUCs).In mice, no adverse effects and no teratogenic effects during gestationwere observed with fexofenadine at dietary doses up to 3730 mg/kg(approximately 15 times the maximum recommended human daily oral doseof fexofenadine hydrochloride 180 mg based on comparison of AUCs). There are noadequate and well controlled studies in pregnant women. Fexofenadineshould be used during pregnancy only if the potential benefit justifiesthe potential risk to the fetus.. Nonteratogenic Effects. Dose-relateddecreases in pup weight gain and survival were observed in rats exposedto an oral dose of 150 mg/kg of terfenadine (approximately timesthe maximum recommended human daily oral dose of fexofenadine hydrochlorideof 180 mg in adults based on comparison of fexofenadine hydrochlorideAUCs).. NURSING MOTHERS. It is not knownif fexofenadine is excreted in human milk. There are no adequate andwell-controlled studies in women during lactation. Because many drugsare excreted in human milk, caution should be exercised when fexofenadinehydrochloride is administered to nursing woman.. PEDIATRIC USE. The recommendeddose in patients to 11 years of age is based on cross-study comparisonof the pharmacokinetics of fexofenadine hydrochloride in adults andpediatric subjects and on the safety profile of fexofenadine hydrochloridein both adult and pediatric subjects at doses equal to or higher thanthe recommended doses.The safety of fexofenadine hydrochloride tablets at dose of 30mg twice daily has been demonstrated in 438 pediatric subjects to11 years of age in two placebo-controlled 2-week seasonal allergicrhinitis trials. The safety of fexofenadine hydrochloride for thetreatment of chronic idiopathic urticaria in subjects to 11 yearsof age is based on cross-study comparison of the pharmacokineticsof fexofenadine hydrochloride in adult and pediatric subjects andon the safety profile of fexofenadine in both adult and pediatricsubjects at doses equal to or higher than the recommended dose.The effectiveness offexofenadine hydrochloride for the treatment of seasonal allergicrhinitis in subjects to 11 years of age was demonstrated in1 trial (n=411) in which fexofenadine hydrochloride tablets 30 mgtwice daily significantly reduced total symptom scores compared toplacebo, along with extrapolation of demonstrated efficacy in subjectsaged 12 years and above, and the pharmacokinetic comparisons in adultsand children. The effectiveness of fexofenadine hydrochloride forthe treatment of chronic idiopathic urticaria in patients to 11years of age is based on an extrapolation of the demonstrated efficacyof fexofenadine hydrochloride in adults with this condition and thelikelihood that the disease course, pathophysiology and the drugseffect are substantially similar in children to that of adult patients.Three clinical safetystudies comparing 15 mg twice daily (n=85) and 30 mg twice daily (n=330)of an experimental formulation of fexofenadine to placebo (n=430)have been conducted in pediatric subjects aged months to years. Ingeneral, fexofenadine hydrochloride was well tolerated in these studies.No unexpected adverse events were seen given the known safety profileof fexofenadine and likely adverse reactions for this patient population.(See ADVERSE REACTIONS and CLINICAL PHARMACOLOGY.)The safetyand effectiveness of fexofenadine hydrochloride in pediatric patientsunder years of age have not been established.. GERIATRIC USE. Clinical studiesof fexofenadine hydrochloride tablets and capsules did not includesufficient numbers of subjects aged 65 years and over to determinewhether this population responds differently from younger subjects.Other reported clinical experience has not identified differencesin responses between the geriatric and younger subjects. This drugis known to be substantially excreted by the kidney, and the riskof toxic reactions to this drug may be greater in patients with impairedrenal function. Because elderly patients are more likely to have decreasedrenal function, care should be taken in dose selection, and it maybe useful to monitor renal function. (See CLINICAL PHARMACOLOGY).

PREGNULLNCY SECTION.


PREGNULLNCY. Teratogenic Effects. Category C.There was no evidence of teratogenicity in rats or rabbits at oraldoses of terfenadine up to 300 mg/kg (which led to fexofenadine exposuresthat were approximately and 30 times, respectively, the exposurefrom the maximum recommended human daily oral dose of fexofenadinehydrochloride of 180 mg based on comparison of AUCs).In mice, no adverse effects and no teratogenic effects during gestationwere observed with fexofenadine at dietary doses up to 3730 mg/kg(approximately 15 times the maximum recommended human daily oral doseof fexofenadine hydrochloride 180 mg based on comparison of AUCs). There are noadequate and well controlled studies in pregnant women. Fexofenadineshould be used during pregnancy only if the potential benefit justifiesthe potential risk to the fetus.. Nonteratogenic Effects. Dose-relateddecreases in pup weight gain and survival were observed in rats exposedto an oral dose of 150 mg/kg of terfenadine (approximately timesthe maximum recommended human daily oral dose of fexofenadine hydrochlorideof 180 mg in adults based on comparison of fexofenadine hydrochlorideAUCs).

SPL UNCLASSIFIED SECTION.


Mechanism of Action. Fexofenadine hydrochloride,the major active metabolite of terfenadine, is an antihistamine withselective peripheral H1-receptor antagonist activity. Bothenantiomers of fexofenadine hydrochloride displayed approximatelyequipotent antihistaminic effects. Fexofenadine hydrochloride inhibitedantigen-induced bronchospasm in sensitized guinea pigs and histaminerelease from peritoneal mast cells in rats. The clinical significanceof these findings is unknown. In laboratory animals, no anticholinergicor alpha1-adrenergic blocking effects were observed. Moreover,no sedative or other central nervous system effects were observed.Radiolabeled tissue distribution studies in rats indicated that fexofenadinedoes not cross the blood-brain barrier.

TERATOGENIC EFFECTS SECTION.


Teratogenic Effects. Category C.There was no evidence of teratogenicity in rats or rabbits at oraldoses of terfenadine up to 300 mg/kg (which led to fexofenadine exposuresthat were approximately and 30 times, respectively, the exposurefrom the maximum recommended human daily oral dose of fexofenadinehydrochloride of 180 mg based on comparison of AUCs).In mice, no adverse effects and no teratogenic effects during gestationwere observed with fexofenadine at dietary doses up to 3730 mg/kg(approximately 15 times the maximum recommended human daily oral doseof fexofenadine hydrochloride 180 mg based on comparison of AUCs). There are noadequate and well controlled studies in pregnant women. Fexofenadineshould be used during pregnancy only if the potential benefit justifiesthe potential risk to the fetus.