ALLEGRA-D® 12 HOUR (fexofenadine hydrochloride and pseudoephedrine hydrochloride)Extended-Release Tablets for oral administration contain 60 mg fexofenadinehydrochloride for immediate release and 120 mg pseudoephedrine hydrochloridefor extended release. Tablets also contain as excipients: microcrystallinecellulose, pregelatinized starch, croscarmellose sodium, magnesiumstearate, carnauba wax, stearic acid, silicon dioxide, hypromelloseand polyethylene glycol.
Fexofenadine hydrochloride, one of the active ingredients of ALLEGRA-D12 HOUR, is a histamine H1-receptor antagonist with thechemical name (±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl benzeneacetic acid hydrochloride and the followingchemical structure:
The molecular weight is 538.13 and the empirical formula is C32H39NO4•HCl. Fexofenadine hydrochlorideis a white to off-white crystalline powder. It is freely soluble inmethanol and ethanol, slightly soluble in chloroform and water, andinsoluble in hexane. Fexofenadine hydrochloride is a racemate andexists as a zwitterion in aqueous media at physiological pH.
Pseudoephedrine hydrochloride,the other active ingredient of ALLEGRA-D 12 HOUR, is an adrenergic(vasoconstrictor) agent with the chemical name [S-(R*,R*)]-α-[1-(methylamino)ethyl]-benzenemethanolhydrochloride and the following chemical structure:
The molecular weight is 201.70. The molecular formula is C10H15NO•HCl. Pseudoephedrine hydrochloride occursas fine, white to off-white crystals or powder, having a faint characteristicodor. It is very soluble in water, freely soluble in alcohol, andsparingly soluble in chloroform.
Mechanism of Action
Fexofenadine hydrochloride,the major active metabolite of terfenadine, is an antihistamine withselective peripheral H1-receptor antagonist activity. Fexofenadinehydrochloride inhibited antigen-induced bronchospasm in sensitizedguinea pigs and histamine release from peritoneal mast cells in rats.In laboratory animals, no anticholinergic or alpha1-adrenergic-receptorblocking effects were observed. Moreover, no sedative or other centralnervous system effects were observed. Radiolabeled tissue distributionstudies in rats indicated that fexofenadine does not cross the blood-brainbarrier.
Pseudoephedrinehydrochloride is an orally active sympathomimetic amine and exertsa decongestant action on the nasal mucosa. Pseudoephedrine hydrochlorideis recognized as an effective agent for the relief of nasal congestiondue to allergic rhinitis. Pseudoephedrine produces peripheral effectssimilar to those of ephedrine and central effects similar to, butless intense than, amphetamines. It has the potential for excitatoryside effects. At the recommended oral dose, it has little or no pressoreffect in normotensive adults.
Pharmacokinetics
The pharmacokineticsof fexofenadine hydrochloride in subjects with seasonal allergic rhinitiswere similar to those in healthy volunteers.
Absorption
The pharmacokineticsof fexofenadine hydrochloride and pseudoephedrine hydrochloride whenadministered separately have been well characterized. Fexofenadinepharmacokinetics were linear for oral doses of fexofenadine hydrochlorideup to a total daily dose of 240 mg (120 mg twice daily). Peak fexofenadineplasma concentrations were similar between adolescent (12–16years of age) and adult subjects.
The bioavailability of fexofenadine hydrochloride and pseudoephedrinehydrochloride from ALLEGRA-D 12 HOUR Extended-Release Tablets is similarto that achieved with separate administration of the components. Coadministrationof fexofenadine and pseudoephedrine does not significantly affectthe bioavailability of either component.
Fexofenadine hydrochloride was rapidly absorbed following single-doseadministration of the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrinehydrochloride tablet with median time to mean maximum fexofenadineplasma concentration of 191 ng/mL occurring 2 hours post-dose. Pseudoephedrinehydrochloride produced a mean single-dose pseudoephedrine peak plasmaconcentration of 206 ng/mL which occurred 6 hours post-dose. Followingmultiple dosing to steady-state, a fexofenadine peak concentrationof 255 ng/mL was observed 2 hours post-dose. Following multiple dosingto steady-state, a pseudoephedrine peak concentration of 411 ng/mLwas observed 5 hours post-dose. The administration of ALLEGRA-D 12HOUR with a high fat meal decreased the bioavailability of fexofenadineby approximately 50% (AUC 42% and Cmax 46%). Time to maximum concentration(Tmax) was delayed by 50%. The rate or extent of pseudoephedrineabsorption was not affected by food. Therefore, ALLEGRA-D 12 HOURshould be taken on an empty stomach with water (see DOSAGE AND ADMINISTRATION).
Distribution
Fexofenadineis 60% to 70% bound to plasma proteins, primarily albumin and α1-acid glycoprotein. The protein binding of pseudoephedrinein humans is not known. Pseudoephedrine hydrochloride is extensivelydistributed into extravascular sites (apparent volume of distributionbetween 2.6 and 3.5 L/kg).
Metabolism
Approximately5% of the total dose of fexofenadine hydrochloride and less than 1%of the total oral dose of pseudoephedrine hydrochloride were eliminatedby hepatic metabolism.
Elimination
The meanelimination half-life of fexofenadine was 14.4 hours following administrationof 60 mg fexofenadine hydrochloride, twice daily, to steady-statein healthy volunteers. Human mass balance studies documented a recoveryof approximately 80% and 11% of the [14C] fexofenadinehydrochloride dose in the feces and urine, respectively. Because theabsolute bioavailability of fexofenadine hydrochloride has not beenestablished, it is unknown if the fecal component is primarily unabsorbeddrug or the result of biliary excretion.
Pseudoephedrine has been shown to have a mean elimination half-lifeof 4–6 hours which is dependent on urine pH. The eliminationhalf-life is decreased at urine pH lower than 6 and may be increasedat urine pH higher than 8.
Special Populations
Pharmacokineticsin special populations (for renal, hepatic impairment, and age), obtainedafter a single dose of 80 mg fexofenadine hydrochloride, were comparedto those from healthy subjects in a separate study of similar design.
Effect of Age
In older subjects (≥65 years old), peak plasma levels of fexofenadinewere 99% greater than those observed in younger subjects (<65 yearsold). Mean fexofenadine elimination half-lives were similar to thoseobserved in younger subjects.
Renally Impaired
In subjects with mild (creatinine clearance 41–80 mL/min)to severe (creatinine clearance 11–40 mL/min) renal impairment,peak plasma levels of fexofenadine were 87% and 111% greater, respectively,and mean elimination half-lives were 59% and 72% longer, respectively,than observed in healthy volunteers. Peak plasma levels in subjectson dialysis (creatinine clearance ≤10 mL/min) were 82% greaterand half-life was 31% longer than observed in healthy volunteers.
No dataare available on the pharmacokinetics of pseudoephedrine in renally-impairedsubjects. However, most of the oral dose of pseudoephedrine hydrochloride(43–96%) is excreted unchanged in the urine. A decrease inrenal function is, therefore, likely to decrease the clearance ofpseudoephedrine significantly, thus prolonging the half-life and resultingin accumulation.
Based on increases in bioavailability and half-life of fexofenadinehydrochloride and pseudoephedrine hydrochloride, a dose of one tabletonce daily is recommended as the starting dose in patients with decreasedrenal function (see DOSAGEAND ADMINISTRATION).
Hepatically Impaired
The pharmacokinetics of fexofenadine hydrochloride in subjects withhepatic disease did not differ substantially from that observed inhealthy volunteers. The effect on pseudoephedrine pharmacokineticsis unknown.
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 mg and 40 mg fexofenadine hydrochloride demonstrated that thedrug exhibits an antihistamine effect by 1 hour, achieves maximumeffect at 2–3 hours, and an effect is still seen at 12 hours.There was no evidence of tolerance to these effects after 28 daysof dosing. The clinical significance of these observations is unknown.
Effects on QTc
In dogs(30 mg/kg orally twice daily for 5 days) and rabbits (10 mg/kg intravenouslyover 1 hour), fexofenadine hydrochloride did not prolong QTc at plasma concentrations that were at least 17 and 38 times, respectively,the therapeutic plasma concentrations in man (based on a 60 mg twice daily fexofenadine hydrochloride dose). No effect was observed oncalcium channel current, delayed K+ channel current, oraction potential duration in guinea pig myocytes, Na+ currentin rat neonatal myocytes, or on the delayed rectifier K+ channel cloned from human heart at concentrations up to 1 ×10-5 M of fexofenadine. This concentration was at least21 times the therapeutic plasma concentration in man (based on a 60mg twice daily fexofenadine hydrochloride dose).
No statistically significant increase in mean QTc intervalcompared to placebo was observed in 714 subjects with seasonal allergicrhinitis given fexofenadine hydrochloride capsules in doses of 60mg to 240 mg twice daily for 2 weeks or in 40 healthy volunteers givenfexofenadine hydrochloride as an oral solution at doses up to 400mg twice daily for 6 days.
A 1-year study designed to evaluate safety and tolerability of 240mg of fexofenadine hydrochloride (n=240) compared to placebo (n=237)in healthy volunteers, did not reveal a statistically significantincrease in the mean QTc interval for the fexofenadinehydrochloride treated group when evaluated pretreatment and after1, 2, 3, 6, 9, and 12 months of treatment.
Administration of the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrinehydrochloride combination tablet for approximately 2 weeks to 213subjects with seasonal allergic rhinitis demonstrated no statisticallysignificant increase in the mean QTc interval comparedto fexofenadine hydrochloride administered alone (60 mg twice daily,n=215), or compared to pseudoephedrine hydrochloride (120 mg twicedaily, n=215) administered alone.
Clinical Studies
In a 2-week, multicenter,randomized, double-blind, active-controlled trial in subjects 12–65years of age with seasonal allergic rhinitis due to ragweed allergy(n=651), the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrinehydrochloride combination tablet administered twice daily significantlyreduced the intensity of sneezing, rhinorrhea, itchy nose/palate/throat,itchy/watery/red eyes, and nasal congestion.
In three, 2-week, multicenter, randomized, double-blind, placebo-controlledtrials in subjects 12–68 years of age with seasonal allergicrhinitis (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 general, there wasno additional reduction in total symptom scores with higher dosesof fexofenadine hydrochloride up to 240 mg twice daily. Although thenumber of subjects in some of the subgroups was small, there wereno significant differences in the effect of fexofenadine hydrochlorideacross subgroups of subjects defined by gender, age, and race. Onsetof action for reduction in total symptom scores, excluding nasal congestion,was observed at 60 minutes compared to placebo following a single60 mg fexofenadine hydrochloride dose administered to subjects withseasonal allergic rhinitis who were exposed to ragweed pollen in anenvironmental exposure unit.
ALLEGRA-D 12 HOUR Extended-ReleaseTablets are indicated for the relief of symptoms associated with seasonalallergic rhinitis in adults and children 12 years of age and older.Symptoms treated effectively include sneezing, rhinorrhea, itchy nose/palate/and/or throat, itchy/watery/red eyes, and nasal congestion.
ALLEGRA-D 12 HOUR should be administeredwhen both the antihistaminic properties of fexofenadine hydrochlorideand the nasal decongestant properties of pseudoephedrine hydrochlorideare desired (see CLINICALPHARMACOLOGY).
ALLEGRA-D 12 HOUR is contraindicatedin patients with known hypersensitivity to any of its ingredients.
Due to its pseudoephedrine component,ALLEGRA-D 12 HOUR is contraindicated in patients with narrow-angleglaucoma or urinary retention, and in patients receiving monoamineoxidase (MAO) inhibitor therapy or within fourteen (14) days of stoppingsuch treatment (see Drug Interactions section). It is also contraindicated in patients with severe hypertension,or severe coronary artery disease, and in those who have shown idiosyncrasyto its components, to adrenergic agents, or to other drugs of similarchemical structures. Manifestations of patient idiosyncrasy to adrenergicagents include: insomnia, dizziness, weakness, tremor, or arrhythmias.
Sympathomimetic amines shouldbe used with caution in patients with hypertension, diabetes mellitus,ischemic heart disease, increased intraocular pressure, hyperthyroidism,renal impairment, or prostatic hypertrophy (see CONTRAINDICATIONS). Sympathomimeticamines may produce central nervous system stimulation with convulsionsor cardiovascular collapse with accompanying hypotension.
General
Patients with decreasedrenal function should be given a lower initial dose (one tablet perday) because they have reduced elimination of fexofenadine and pseudoephedrine(see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Information for Patients
Patients takingALLEGRA-D 12 HOUR tablets should receive the following information:ALLEGRA-D 12 HOUR tablets are prescribed for the relief of symptomsof seasonal allergic rhinitis. Patients should be instructed to takeALLEGRA-D 12 HOUR tablets only as prescribed. Do not exceed the recommended dose. If nervousness, dizziness,or sleeplessness occur, discontinue use and consult the doctor. Patientsshould also be advised against the concurrent use of ALLEGRA-D 12HOUR tablets with over-the-counter antihistamines and decongestants.
The product should notbe used by patients who are hypersensitive to it or to any of itsingredients. Due to its pseudoephedrine component, this product shouldnot be used by patients with narrow-angle glaucoma, urinary retention,or by patients receiving a monoamine oxidase (MAO) inhibitor or within14 days of stopping use of MAO inhibitor. It also should not be usedby patients with severe hypertension or severe coronary artery disease.
Patients should be toldthat this product should be used in pregnancy or lactation only ifthe potential benefit justifies the potential risk to the fetus ornursing infant. Patients should be advised to take the tablet on anempty stomach with water. Patients should be directed to swallow thetablet whole. Patients should be cautioned not to break or chew thetablet. Patients should also be instructed to store the medicationin a tightly closed container in a cool, dry place, away from children.
Patients should be toldthat the inactive ingredients may occasionally be eliminated in thefeces in a form that may resemble the original tablet (see DOSAGE AND ADMINISTRATION).
Drug Interactions
Fexofenadine hydrochlorideand pseudoephedrine hydrochloride do not influence the pharmacokineticsof each other when administered concomitantly.
Fexofenadine has been shown to exhibit minimal (ca. 5%) metabolism.However, co-administration of fexofenadine hydrochloride with eitherketoconazole or erythromycin led to increased plasma concentrationsof fexofenadine. Fexofenadine had no effect on the pharmacokineticsof either erythromycin or ketoconazole. In 2 separate studies, fexofenadinehydrochloride 120 mg twice daily (twice the recommended dose) wasco-administered with erythromycin 500 mg every 8 hours or ketoconazole400 mg once daily under steady-state conditions to healthy volunteers(n=24, each study). No differences in adverse events or QTc interval were observed when subjects were administered fexofenadinehydrochloride alone or in combination with either erythromycin orketoconazole. The findings of these studies are summarized in thefollowing table.
| Concomitant Drug | CmaxSS (Peakplasma concentration) | AUCSS(0–12h) (Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) | +82% | +109% |
| Ketoconazole (400 mg once daily) | +135% | +164% |
The changes inplasma levels were within the range of plasma levels achieved in adequateand well-controlled clinical trials.
The mechanismof these interactions has been evaluated in in vitro, in situ, and in vivo animal models.These studies indicate that ketoconazole or erythromycin co-administrationenhances fexofenadine gastrointestinal absorption. This observed increasein the 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.
Due to the pseudoephedrine component, ALLEGRA-D 12 HOUR is contraindicatedin patients taking monoamine oxidase inhibitors and for 14 days afterstopping use of an MAO inhibitor. Concomitant use with antihypertensivedrugs which interfere with sympathetic activity (e.g., methyldopa,mecamylamine, and reserpine) may reduce their antihypertensive effects.Increased ectopic pacemaker activity can occur when pseudoephedrineis used concomitantly with digitalis. Care should be taken in theadministration of ALLEGRA-D 12 HOUR concomitantly with other sympathomimeticamines because combined effects on the cardiovascular system may beharmful to the patient (see WARNINGS).
Drug Interactions with Antacids
Administrationof 120 mg of fexofenadine hydrochloride (2 × 60 mg capsule) within15 minutes of an aluminum and magnesium containing antacid (Maalox®)decreased fexofenadine AUC by 41% and Cmax by 43%. ALLEGRA-D12 HOUR should not be taken closely in time with aluminum and magnesiumcontaining antacids.
Interactions with Fruit Juices
Fruit juicessuch as grapefruit, orange and apple may reduce the bioavailabilityand exposure of fexofenadine. This is based on the results from 3clinical studies using histamine induced skin wheals and flares coupledwith population pharmacokinetic analysis. The size of wheal and flarewere significantly 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 a bioequivalence study, the bioavailability offexofenadine was reduced by 36%. Therefore, to maximize the effectsof fexofenadine, it is recommended that ALLEGRA-D 12 HOUR should betaken with water (see DOSAGE AND ADMINISTRATION).
Carcinogenesis, Mutagenesis, Impairment of Fertility
There are no animalor in vitro studies on thecombination product fexofenadine hydrochloride and pseudoephedrinehydrochloride to evaluate carcinogenesis, mutagenesis, or impairmentof fertility.
The carcinogenic potential and reproductive toxicity of fexofenadinehydrochloride were assessed using terfenadine studies with adequatefexofenadine exposure (area-under-the plasma concentration versustime curve [AUC]). No evidence of carcinogenicity was observed whenmice and rats were given daily oral doses up to 150 mg/kg of terfenadinefor 18 and 24 months, respectively. In both species, 150 mg/kg ofterfenadine produced AUC values of fexofenadine that were approximately3 times the human AUC at the maximum recommended human daily oraldose of ALLEGRA-D 12 HOUR.
Two-year feeding studies in rats and mice conducted under the auspicesof the National Toxicology Program (NTP) demonstrated no evidenceof carcinogenic potential with ephedrine sulfate, a structurally relateddrug with pharmacological properties similar to pseudoephedrine, atdoses up to 10 and 27 mg/kg, respectively (less than the maximum recommendedhuman daily oral dose of pseudoephedrine hydrochloride on a mg/m2 basis).
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.
Reproduction and fertility studies with terfenadine in rats produced no effect on male or female fertility at oral doses up to 300 mg/kg/day.However, reduced implants and post implantation losses were reportedat 300 mg/kg. A reduction in implants was also observed at an oraldose of 150 mg/kg/day. Oral doses of 150 and 300 mg/kg of terfenadineproduced AUC values of fexofenadine that were approximately 4 timesthe AUC at the maximum recommended human daily oral dose of ALLEGRA-D12 HOUR. In mice, fexofenadine produced no effect on male or femalefertility at average dietary doses up to 4438 mg/kg (approximately15 times the maximum recommended human daily oral dose of ALLEGRA-D12 HOUR based on comparison of the AUCs).
Pregnancy
Teratogenic Effects
CategoryC. Terfenadine alone was not teratogenic in rats and rabbits at oraldoses up to 300 mg/kg; 300 mg/kg of terfenadine produced fexofenadineAUC values that were approximately 4 and 30 times, respectively, theAUC at the maximum recommended human daily oral dose of ALLEGRA-D12 HOUR.
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 ALLEGRA-D 12 HOUR based on comparison of the AUCs).
The combinationof terfenadine and pseudoephedrine hydrochloride in a ratio of 1:2by weight was studied in rats and rabbits. In rats, an oral combinationdose of 150/300 mg/kg produced reduced fetal weight and delayed ossificationwith a finding of wavy ribs. The dose of 150 mg/kg of terfenadinein rats produced an AUC value of fexofenadine that was approximately4 times the AUC at the maximum recommended human daily oral dose ofALLEGRA-D 12 HOUR. The dose of 300 mg/kg of pseudoephedrine hydrochloridein rats was approximately 10 times the maximum recommended human dailyoral dose of ALLEGRA-D 12 HOUR on a mg/m2 basis. In rabbits,an oral combination dose of 100/200 mg/kg produced decreased fetalweight. By extrapolation, the AUC of fexofenadine for 100 mg/kg orallyof terfenadine was approximately 10 times the AUC at the maximum recommendedhuman daily oral dose of ALLEGRA-D 12 HOUR. The dose of 200 mg/kgof pseudoephedrine hydrochloride was approximately 15 times the maximumrecommended human daily oral dose of ALLEGRA-D 12 HOUR on a mg/m2 basis.
There are no adequate and well-controlled studies in pregnant women.ALLEGRA-D 12 HOUR should be used during pregnancy only if the potentialbenefit justifies the 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; this dose produced anAUC of fexofenadine that was approximately 4 times the AUC at themaximum recommended human daily oral dose of ALLEGRA-D 12 HOUR.
Nursing Mothers
It is not knownif fexofenadine is excreted in human milk. Because many drugs areexcreted in human milk, caution should be used when fexofenadine hydrochlorideis administered to a nursing woman. Pseudoephedrine hydrochlorideadministered alone distributes into breast milk of lactating humanfemales. Pseudoephedrine concentrations in milk are consistently higherthan those in plasma. The total amount of drug in milk as judged byAUC is 2 to 3 times greater than the plasma AUC. The fraction of apseudoephedrine dose excreted in milk is estimated to be 0.4% to 0.7%.A decision should be made whether to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother.Caution should be exercised when ALLEGRA-D 12 HOUR is administeredto nursing women.
Pediatric Use
Safety and effectivenessof ALLEGRA-D 12 HOUR in children below the age of 12 years have notbeen established. In addition, the doses of the individual componentsin ALLEGRA-D 12 HOUR exceed the recommended individual doses for pediatricpatients under 12 years of age. ALLEGRA-D 12 HOUR is not recommendedfor pediatric patients under 12 years of age.
Geriatric Use
Clinical studiesof ALLEGRA-D 12 HOUR did not include sufficient numbers of subjectsaged 65 and older to determine whether they respond differently fromyounger subjects. Other reported clinical experience has not identifieddifferences in responses between the elderly and younger subjects,although the elderly are more likely to have adverse reactions tosympathomimetic amines.
The pseudoephedrine component of ALLEGRA-D 12 HOUR is known to besubstantially excreted by the kidney, and the risk of toxic reactionsto this drug may be greater in patients with impaired renal function.Because elderly patients are more likely to have decreased renal function,care should be taken in dose selection, and it may be useful to monitorrenal function.
ALLEGRA-D 12 HOUR
In one clinicaltrial (n=651) in which 215 subjects with seasonal allergic rhinitisreceived the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrinehydrochloride combination tablet twice daily for up to 2 weeks, adverseevents were similar to those reported either in subjects receivingfexofenadine hydrochloride 60 mg alone (n=218 subjects) or in subjectsreceiving pseudoephedrine hydrochloride 120 mg alone (n=218). A placebogroup was not included in this study.
The percent of subjects who withdrew prematurely because of adverseevents was 3.7% for the fexofenadine hydrochloride/pseudoephedrinehydrochloride combination group, 0.5% for the fexofenadine hydrochloridegroup, and 4.1% for the pseudoephedrine hydrochloride group. All adverseevents that were reported by greater than 1% of subjects who receivedthe recommended daily dose of the fexofenadine hydrochloride/pseudoephedrinehydrochloride combination are listed in the following table.
| Adverse Experience | 60 mg Fexofenadine Hydrochloride/120mg Pseudoephedrine Hydrochloride Combination Tablet Twice Daily (n=215) | Fexofenadine Hydrochloride 60 mg Twice Daily (n=218) | Pseudoephedrine Hydrochloride 120 mg Twice Daily (n=218) |
|---|---|---|---|
| Headache | 13.0% | 11.5% | 17.4% |
| Insomnia | 12.6% | 3.2% | 13.3% |
| Nausea | 7.4% | 0.5% | 5.0% |
| Dry Mouth | 2.8% | 0.5% | 5.5% |
| Dyspepsia | 2.8% | 0.5% | 0.9% |
| Throat Irritation | 2.3% | 1.8% | 0.5% |
| Dizziness | 1.9% | 0.0% | 3.2% |
| Agitation | 1.9% | 0.0% | 1.4% |
| Back Pain | 1.9% | 0.5% | 0.5% |
| Palpitation | 1.9% | 0.0% | 0.9% |
| Nervousness | 1.4% | 0.5% | 1.8% |
| Anxiety | 1.4% | 0.0% | 1.4% |
| Upper Respiratory Infection | 1.4% | 0.9% | 0.9% |
| Abdominal Pain | 1.4% | 0.5% | 0.5% |
Many of the adverseevents occurring in the fexofenadine hydrochloride/pseudoephedrinehydrochloride combination group were adverse events also reportedpredominately in the pseudoephedrine hydrochloride group, such asinsomnia, headache, nausea, dry mouth, dizziness, agitation, nervousness,anxiety, and palpitation.
Fexofenadine Hydrochloride
In placebo-controlledclinical trials, which included 2461 subjects receiving fexofenadinehydrochloride at doses of 20 mg to 240 mg twice daily, adverse eventswere similar in fexofenadine hydrochloride and placebo-treated subjects.The incidence of adverse events, including drowsiness, was not doserelated and was similar across subgroups defined by age, gender, andrace. The percent of subjects who withdrew prematurely because ofadverse events was 2.2% with fexofenadine hydrochloride vs 3.3% withplacebo.
Events that have been reported during controlled clinical trialsinvolving subjects with seasonal allergic rhinitis and chronic idiopathicurticaria at incidences less than 1% and similar to placebo and havebeen rarely reported during postmarketing surveillance include: insomnia,nervousness, and sleep disorders or paroniria. In rare cases, rash,urticaria, pruritus and hypersensitivity reactions with manifestationssuch as angioedema, chest tightness, dyspnea, flushing and systemicanaphylaxis have been reported.
Pseudoephedrine Hydrochloride
Pseudoephedrinehydrochloride may cause mild CNS stimulation in hypersensitive patients.Nervousness, excitability, restlessness, dizziness, weakness, or insomniamay occur. Headache, drowsiness, tachycardia, palpitation, pressoractivity, cardiac arrhythmias and ischemic colitis have been reported. Sympathomimeticdrugs have also been associated with other untoward effects such asfear, anxiety, tenseness, tremor, hallucinations, seizures, pallor,respiratory difficulty, dysuria, and cardiovascular collapse.
Most reports of fexofenadinehydrochloride overdose contain limited information. However, dizziness,drowsiness, and dry mouth have been reported. For the pseudoephedrinehydrochloride component of ALLEGRA-D 12 HOUR, information on acuteoverdose is limited to the marketing history of pseudoephedrine hydrochloride.Single doses of fexofenadine hydrochloride up to 800 mg (6 healthyvolunteers at this dose level), and doses up to 690 mg twice dailyfor one month (3 healthy volunteers at this dose level), were administeredwithout the development of clinically significant adverse events.
In large doses, sympathomimeticsmay give rise to giddiness, headache, nausea, vomiting, sweating,thirst, tachycardia, precordial pain, palpitations, difficulty inmicturition, muscular weakness and tenseness, anxiety, restlessness,and insomnia. Many patients can present a toxic psychosis with delusionsand hallucinations. Some may develop cardiac arrhythmias, circulatorycollapse, convulsions, coma, and respiratory failure.
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). The effect of hemodialysis on the removalof pseudoephedrine is unknown.
No deaths occurred in mature mice and rats at oral doses of fexofenadinehydrochloride up to 5000 mg/kg (approximately 170 and 340 times, respectively,the maximum recommended human daily oral dose of ALLEGRA-D 12 HOURon a mg/m2 basis.) The median oral lethal dose in newbornrats was 438 mg/kg (approximately 30 times the maximum recommendedhuman daily oral dose of ALLEGRA-D 12 HOUR on a mg/m2 basis).In dogs, no evidence of toxicity was observed at oral doses up to2000 mg/kg (approximately 450 times the maximum recommended humandaily oral dose on a mg/m2 basis). The oral median lethaldose of pseudoephedrine hydrochloride in rats was 1674 mg/kg (approximately55 times the maximum recommended human daily oral dose of ALLEGRA-D12 HOUR on a mg/m2 basis).
The recommended dose ofALLEGRA-D 12 HOUR Extended-Release Tablets is one tablet twice dailyadministered on an empty stomach with water for adults and children12 years of age and older. It is recommended that the administrationof ALLEGRA-D 12 HOUR with food should be avoided. A dose of one tabletonce daily is recommended as the starting dose in patients with decreasedrenal function. (See CLINICALPHARMACOLOGY and PRECAUTIONS.)
ALLEGRA-D 12 HOURmust be swallowed whole and never crushed or chewed. Occasionally,the inactive ingredients of ALLEGRA-D 12 HOUR may be eliminated inthe feces in a form that may resemble the original tablet. (See PRECAUTIONS, Information for Patients.)
ALLEGRA-D 12 HOUR Extended-ReleaseTablets contain 60 mg fexofenadine hydrochloride for immediate releaseand 120 mg pseudoephedrine hydrochloride for extended release. ALLEGRA-D12 HOUR Extended-Release Tablets are available in high-density polyethylene(HDPE) of:
| Bottles of 10 | NDC 54868-4258-3 |
| Bottles of 20 | NDC 54868-4258-2 |
| Bottles of 30 | NDC 54868-4258-0 |
| Bottles of 60 | NDC 54868-4258-1 |
ALLEGRA-D 12 HOUR is a two-layertablet, one white layer and one tan layer with a clear film coatingon the tablet. The tablets are engraved with "06/012D" on the whitelayer.
Store ALLEGRA-D12 HOUR Extended-Release Tablets at 20–25°C (68–77°F).(See USP Controlled Room Temperature.)
Rev. December 2009
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www.allegra.com
Relabeling and Repackaging by:
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Tulsa, OK 74146
allegra-D 12 Hour
fexofenadine HCl 60mg and
pseudoephedrine HCl 120mg
Extended-Release Tablets
Rx ONLY
Physicians Total Care, Inc.