Allegra (Fexofenadine HCl)

ALLEGRA™

Hoechst Marion Roussel

Fexofenadine HCl

Histamine H1-Receptor Antagonist

Action And Clinical Pharmacology: Fexofenadine, the predominant human and animal active metabolite of terfenadine, is a selective histamine H1-receptor antagonist. In laboratory animals, there is no evidence of local anesthetic, analgesic, anticonvulsant, antidepressant, antidopaminergic, antiserotonergic, anticholinergic, sedative, H2-receptor antagonist, or a1-adrenergic receptor blocking activity. Fexofenadine inhibits antigen-induced bronchospasm in sensitized guinea pigs and histamine release from peritoneal mast cells of the rat. It does not cross the blood-brain barrier in the rat.

Fexofenadine inhibits histamine induced skin wheal and flare responses. Following single and twice daily oral dose administration, antihistaminic effects occur within 1 hour, achieve a maximum at 6 hours, and last a minimum of 12 hours. There is no evidence of tolerance to these effects after 28 days of dosing.

At steady-state with 60 mg b.i.d. dosing, the average percent inhibition of skin wheal was 45.8% and 53.6% for fexofenadine and terfenadine, respectively. The average maximum inhibition and average area under effect curve was similar for both drugs at equivalent doses. Although higher doses, i.e., 180 mg b.i.d. produced somewhat greater inhibition, the average difference was only 10 to 12%. At 12 hours postdose, the average percent inhibition was approximately 30%.

Similar results were observed with the skin flare response, although the average percent inhibition was somewhat higher – 69% and 75%, for 60 mg b.i.d. fexofenadine and terfenadine, respectively. Equivalent doses of both drugs produced comparable maximum inhibition and area under effect curve. The flare area was inhibited greater than 55% at 12 hours postdose.

There was no clear-cut relationship between plasma concentrations of fexofenadine or dose of either fexofenadine or terfenadine. Maximum inhibition was achieved at plasma fexofenadine concentrations of 200 ng/mL.

In randomized, double-blind, placebo-controlled trials, a daily dose of fexofenadine 60 mg b.i.d. was shown to be effective in relieving the symptoms of seasonal allergic rhinitis (trees and grasses in the spring or ragweed pollen in the fall). These symptoms consisted of sneezing, rhinorrhea, itchy nose/palate/throat and itchy, watery, red eyes. There was no statistically significant difference in the treatment effect in subgroups defined by age, gender, race or weight.

There was no direct comparison with terfenadine. However, in studies with similar trial design, the effectiveness of fexofenadine appears to be comparable to that of the parent compound.

Preclinical and clinical evidence indicates that fexofenadine does not prolong the QTc interval (the mechanism underlying the arrhythmias associated with elevated levels of terfenadine). The evidence is derived from in vitro electrophysiological studies, in vivo preclinical studies in dogs and rabbits and a number of clinical trials consisting of 2 definitive QTc studies (n=24 and 40), 2 dose escalation studies (n=24 and 66), 2 drug interaction studies investigating the effects of erythromycin and ketoconazole (n=24 for each study), 2 randomized Phase III clinical trials in patients with fall allergic rhinitis (n=870 subjects treated with fexofenadine), 2 long-term safety studies (n=234 and 217 subjects treated with fexofenadine), and single dose (80 mg) studies in special populations (individuals over 65 years of age, patients with various degrees of renal and hepatic impairment).

Pharmacokinetics: Fexofenadine is rapidly absorbed following oral administration. The single and multiple dose pharmacokinetics of fexofenadine were linear from 20 mg to 120 mg doses. Tmax occurs at approximately 2.6 hours and Cmax is approximately 209 ng/mL following oral administration of a single 60 mg dose.

Following multiple dosing, fexofenadine has an apparent elimination half-life of 11 to 16 hours. Steady-state pharmacokinetic parameters following 60 mg b.i.d. dosing are: AUCss (0-12h)=1 367 ng/mL.h, Cmax=299 ng/mL, Cmin=29 ng/mL, Tmax=1 h.

The pharmacokinetics of fexofenadine in seasonal allergic rhinitis patients are similar to that of otherwise healthy subjects. Peak fexofenadine plasma concentrations were similar between adolescent (12 to 16 years of age) and adult patients.

Metabolism of fexofenadine is negligible. The methyl ester of fexofenadine (3.6% of the dose) and MDL 4829 (1.5% of the dose) were the only potential metabolites of fexofenadine detected.

Following a single 60 mg oral dose, 80% and 11% of the total [4] fexofenadine dose is recovered in the feces and urine, respectively. The principal elimination pathways of fexofenadine are biliary and renal. Fecal excretion of fexofenadine is comprised of biliary excretion and gastrointestinal secretion processes as well as nonabsorbed drug. The contribution of each component is unknown.

The absolute bioavailability of fexofenadine has not been established but is estimated to be approximately 33%. The capsule and tablet formulations are considered to be bioequivalent but the tablet formulation exhibits a greater food effect. The AUC and Cmax of the tablet formulation in the presence of food was reduced to 76% (83% for the capsule) and 75% (89% of the capsule) of the fasted values.

Current theory suggests that fexofenadine absorption is incomplete due to the gate-keeping function of the p-glycoprotein transport system in the intestinal epithelium which reduces both fexofenadine absorption, explaining the low bioavailability, as well as secretes absorbed drug back into the gastrointestinal tract. Since approximately 80% of an orally administered dose is recovered in the feces, primarily as unchanged drug, rather than 67% (100%-33%), this difference is believed to represent fexofenadine secretion from the systemic circulation into the gastrointestinal lumen.

Fexofenadine is 60 to 80% bound to plasma proteins, including serum albumin and a-acid glycoprotein. Protein binding is decreased to 56 to 68% and 56 to 75% in renally and hepatically impaired patients, respectively.

Special Populations: Pharmacokinetics in special populations were determined following a single 80 mg oral dose of fexofenadine. The pharmacokinetics were compared to those from normal subjects in a separate study of similar design. While subjects’ weights were relatively uniform between the studies, the special population patients were older than the healthy, young volunteers. Thus, an age effect may be confounding the pharmacokinetic differences observed.

Renal Impairment: Following a single 80 mg oral dose, renal clearance is decreased to 68, 15 and 3% of the control value (3.63 L/h) in patients with mild to moderate impairment (creatinine clearance 41 to 80 mL/min; n=9), moderate to severe impairment (creatinine clearance 11 to 40 mL/min; n=10) and dialysis patients (creatinine clearance
Hepatic Impairment: The pharmacokinetics of fexofenadine in 14 patients with hepatic disease (moderate, n=9; moderate to severe, n=5), did not differ substantially from that observed in healthy subjects. The lack of effect may be explained by the fact that none of the patients investigated suffered from complete biliary obstruction, as biliary excretion is one of the major elimination pathways for fexofenadine.

Effect of Age: The pharmacokinetics of fexofenadine in healthy elderly individuals (>65 years old, n=20) were different from those observed in healthy younger individuals following a single oral dose of 80 mg fexofenadine. Mean AUC was 63% higher (control value=1 788 ng/mL.h), oral clearance 30% lower (control value=48 L/h), renal clearance 24% less (control value=3.6 L/h), Cmax 68% higher (control value= 248.7 ng/mL) and half-life 10% longer (15.2 h).

Effect of Gender: The steady-state AUC and Cmax values in female subjects (n=20) were 33% and 46% higher, respectively, than those observed in male subjects (n=20). Renal clearance was equivalent. There was no indication of any difference in safety or efficacy.

Drug Interactions: During multiple dose coadministration (fexofenadine 120 mg b.i.d. for 6.5 days plus erythromycin 500 mg t.i.d. for 6.33 days) erythromycin increased AUCss(0-12 h) of fexofenadine from 2 422 to 5 055 ng/mL.h (109%), reduced oral clearance by 51%, extended tmax from 2.2 to 3.7 hours and increased Cmax from 410 to 744 ng/mL (80%) in 20 healthy volunteers. Renal clearance was increased from 3.6 to 4 L/h. Fexofenadine had no effect on the pharmacokinetics of erythromycin.

Ketoconazole coadministration (fexofenadine 120 mg b.i.d. plus ketoconazole 400 mg daily for 7 days) increased AUCss (0-12h) of fexofenadine from 2 100 to 5 547 ng/mL.h (164%), reduced oral clearance by 61% and increased Cmax from 388 to 914 ng/mL (136%) in 24 healthy volunteers. Fexofenadine had no effect on the pharmacokinetics of ketoconazole.

The increased systemic exposure to fexofenadine as a result of erythromycin or ketoconazole co-administration is below that observed with 240 or 400 mg b.i.d. doses (AUCss of 6 935 and 13 578 ng/mL.h, respectively) of fexofenadine, neither of which was associated with any adverse effects.

Indications And Clinical Uses: For the relief of symptoms associated with seasonal allergic rhinitis, such as sneezing, rhinorrhea, lacrimation, itchy, red eyes or itchy nose/palate/throat in adults and children 12 years of age and older.

Contra-Indications: In patients with known hypersensitivity to any of its ingredients.

Drug Interactions: Since fexofenadine does not undergo hepatic biotransformation, it is unlikely to interact with drugs that rely upon hepatic metabolism.

Fexofenadine at twice the recommended dose (120 mg b.i.d.), has been safely coadministered with erythromycin (500 mg q8h) and ketoconazole (400 mg daily) under steady-state conditions in healthy volunteers. No differences in adverse events were reported whether fexofenadine was administered alone or in combination. The coadministration of fexofenadine with erythromycin or ketoconazole resulted in no significant increases in daily mean or maximum QTc interval when analyzed by machine or a cardiologist.

The mechanism(s) underlying the interaction with ketoconazole and erythromycin have not been conclusively established. Preliminary evidence suggests that both ketoconazole and erythromycin decrease fexofenadine secretion into the gastrointestinal tract. Secondarily, erythromycin also appears to decrease biliary clearance. Ketoconazole appears to have negligible effects on biliary or renal clearance of fexofenadine.

The administration of a single 20 mL dose of Maalox suspension followed 15 minutes later by a single oral dose of 120 mg fexofenadine resulted in a significant reduction in fexofenadine bioavailability (41% reduction in AUC(0-30h); 43% reduction in Cmax). This interaction has been explained on the basis that up to 27.8% of fexofenadine is physically bound to Maalox in the stomach at pH of 4 or greater.

Pretreatment with omeprazole (20 mg 10 hour prior to and 40 mg 1 hour prior to a single dose of 120 mg fexofenadine) did not alter the bioavailability of fexofenadine.

Pregnancy: The reproduction toxicology data for fexofenadine rely solely upon those that have been obtained with terfenadine (Seldane) and linked by appropriate bridging pharmacokinetic studies. There was no evidence of teratogenicity in rats or rabbits at fexofenadine plasma AUC values 4 and 37 times the human therapeutic value, respectively. Dose-related decreases in pup weight gain and survival were observed in rats exposed to fexofenadine plasma AUC values equal to or greater than 3 times the human therapeutic value (obtained at steady state with 60 mg b.i.d. dosing).

There are no adequate and well-controlled studies in pregnant women. Fexofenadine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation : There are no adequate and well controlled studies in women during lactation. However, when terfenadine was administered to nursing mothers, fexofenadine was found to cross into human breast milk. Therefore, fexofenadine is not recommended for breast-feeding women.

Children: The safety and effectiveness of fexofenadine in children under 12 years of age have not been established. In a randomized, controlled, clinical trial setting, a total of 205 subjects between the ages of 12 to 16 years were administered doses of fexofenadine ranging from 20 to 240 mg b.i.d. for 2 weeks. Adverse events were similar in this group compared to subjects above 16 years of age.

Geriatrics: In randomized, controlled, clinical trials, 42 patients age 60 to 68 years were administered doses of fexofenadine ranging from 20 to 240 mg b.i.d. for 2 weeks. Adverse events are similar in this group compared to patients under 60 years of age. Nevertheless, the pharmacokinetics of fexofenadine are altered (increased bioavailability) in individuals over 65 years of age (see Pharmacology, Pharmacokinetics).

Special Populations: The pharmacokinetics of fexofenadine are altered in individuals with renal impairment (see Pharmacology, Pharmacokinetics). Based on increases in bioavailability and half-life, a dose of 60 mg once daily is recommended as the starting dose in patients with decreased renal function.

Moderate to severe hepatic disease does not affect the pharmacokinetics of fexofenadine substantially.

In surgically manipulated intestinal tissue (e.g., bowel resection) as well as in inflamed intestinal tissue, p-glycoprotein expression is actually increased. Thus, the oral bioavailability of fexofenadine could possibly be reduced in these disease states.

Adverse Reactions: In 4, 2-week, placebo-controlled trials involving seasonal allergic rhinitis (SAR) patients, adverse events were similar in fexofenadine and placebo-treated patients. There was no dose-related increase in adverse events, including drowsiness, when administered up to 4 times the recommended therapeutic dose. Adverse event rates were similar among subgroups defined by age, gender, and race. The rate of premature withdrawal because of adverse events was 2% (48/2 346) with fexofenadine vs 3.2% (22/685) with placebo.

Central and Peripheral Nervous Systems: insomnia, dizziness.

Gastrointestinal: diarrhea, dyspepsia, abdominal pain, flatulence, vomiting.

Respiratory: epistaxis, throat irritation.

Metabolic and Nutritional: thirst.

Psychiatric: appetite increase, nervousness, agitation, nightmares.

Autonomic Nervous System: dry mouth, dryness of mucous membranes.

Skin and Appendages: pruritus, rash.

Urinary: urinary frequency.

Heart Rate and Rhythm: tachycardia, palpitation.

Infectious Disease: viral infection.

Vision: blurred vision.

Musculoskeletal: chest pain.

Hearing and Vestibular: earache.

The frequency and magnitude of laboratory abnormalities were similar with fexofenadine and placebo.

Two double-blind, placebo-controlled, parallel group, long-term safety studies were conducted in healthy volunteers. In 1 study, 217 subjects received 60 mg fexofenadine b.i.d. for 6 months, and in the other, 234 subjects received 240 mg fexofenadine once daily for 12 months. The nature and incidence of adverse events observed were similar for fexofenadine and placebo, and the types of adverse events reported in these 2 long-term studies were not different from those observed in the Phase III clinical trials. There were no particular patterns observed in the occurrence of treatment related adverse events in demographic subgroups with respect to gender, age and race. There were no statistically significant changes in measured ECG parameters or vital signs from baseline to the last visit in subjects treated with fexofenadine vs placebo.

In U.S. postmarketing surveillance, 1 case of congestive heart failure has been reported. One case of atrial fibrillation has been reported in clinical studies. A definite cause and effect relationship has not been established.

Symptoms And Treatment Of Overdose: Symptoms: There is no clinical experience with fexofenadine overdose. Single doses of fexofenadine up to 800 mg (n=6 healthy male volunteers; highest Cmax= 12 250 ng/mL; mean Cmax and AUC=6 383 ng/mL and 28 396 ng/mL.h, respectively) and doses up to 690 mg b.i.d. (n=3 healthy male volunteers; mean AUCss=21 706 ng/mL.h; mean Cmax,ss=4 677 ng/mL) for 1 month were investigated without the development of clinically significant adverse events. The maximum tolerated dose of fexofenadine was not reached. Overall, there was no evidence of QTc prolongation at doses 11 times the recommended therapeutic dose.

Treatment: In the event of overdose, standard measures to remove any unabsorbed drug should be considered. Symptomatic and supportive treatment is recommended.

Hemodialysis did not effectively remove fexofenadine from blood (up to 1.7% removed) following terfenadine administration.

Dosage And Administration: Adults and Children 12 years and older: The recommended dose is 60 mg twice daily.

A dose of 60 mg daily is recommended as a starting dose in individuals with decreased renal function.

Children under 12 years: Safety and effectiveness of fexofenadine in children under the age of 12 have not been established.

Availability And Storage: Each peach, round, double convex tablet, plain on one side and debossed on the other side with “60”, contains fexofenadine HCl 60 mg. Nonmedicinal ingredients: croscarmellose sodium, gelatin, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, pink and yellow iron oxide blend, povidone, polyethylene glycol, silicon dioxide, starch and titanium dioxide. Blister packs of 12, 24 and 36.

Store at 15 to 30°C in a dry place.

ALLEGRA™ Hoechst Marion Roussel Fexofenadine HCl Histamine H1-Receptor Antagonist

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