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Telfast D

Fexofenadine HCl 60 mg and
pseudoephedrine HCI 120 mg
Extended-Release Tablets

TELFAST D (fexofenadine hydrochloride and pseudoephedrine hydrochloride) Extended Release Tablets for oral administration contain 60 mg fexofenadine hydrochloride for immediate release and 120 mg pseudoephedrine hydrochloride for extended release. Tablets also contain as excipients : micro crystalline cellulose, prege-latinized starch, croscarmellose sodium magnesium stearate, car-nauba wax, stearic acid, silicon dioxide, hydroxypropyl methyl cellulose and polyethylene glycol.

Fexofenadine hydrochloride, one of the active ingredients of TELFAST D, is a histamine H1-receptor antagonist with the chemical name (+)-4-[1-hydroxy-4-[4-(hydroxy diphenylmethyl)-1-piperi-dinyl]-(butyl]-α, α-dimethyl benzene acetic acid hydrochloride and the following chemical structure:

The molecular weight is 538.13 and the empirical formula is C32H39-NO4.HCI. Fexofenadine hydrochloride is a white to off white crystalline powder. It is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane. Fexofenadine hydrochloride is a racemate and exists as a zwitterion in aqueous media at physiological pH.
Pseudoephedrine hydrochloride the other active ingredient of TELFAST D, is an adrenergic (vaso-constrictor) agent with the chemical name [S-(R*,R*)]-α-[1-(methyl-amino)ethyl]-benzene-methanol hydrochloride and the following chemical structure:

The molecular weight is 201.70. The molecular formula is C10H15NO.HCI. Pseudoephedrine hydrochloride occurs as fine, white to off white crystals or powder, having a faint characteristic odor. It is very soluble in water, freely soluble in alcohol, and sparingly soluble in chloroform.

Mechanism of Action
Fexofenadine hydrochloride, the major active metabolite of terfenadine, is an antihistamine with selective peripheral H1- receptor antagonist activity. Fexofenadine hydrochloride inhibited antigen induced bronchospasm in sensitized guinea pigs and histamine release from peritoneal mast cells in rats. In laboratory animals, no anticholinergic or alpha1-adrenergic-receptor locking effects were observed. Moreover, no sedative or other central nervous system effects were observed. Radiolabeled tissue distribution studies in rats indicated that fexofenadine does not cross the blood brain barrier.

Pseudoephedrine hydrochloride is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine hydrochloride is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects. At the recommended oral dose, it has little or no pressor effect in normotensive adults.

The pharmacokinetics of fexofenadine hydrochloride and Pseudoephedrine hydrochloride when administered separately have been well characterized. Fexofenadine pharmacokinetics were linear for oral doses of fexofenadine hydrochloride up to 120 mg twice daily. The mean elimination half life of fexofenadine was 14.4 hours following administration of 60 mg fexofenadine hydrochloride, twice-daily, to steady state in normal volunteers. Human mass balance studies documented a recovery of approximately 80% and 11% of the [14C] fexofenadine hydrochloride dose in the feces and urine, respectively. Approximately 5% of the total dose was metabolized. Because the absolute bioavailability of fexofenadine hydrochloride has not been established, it is unknown if the fecal component is unabsorbed drug or the result of biliary excretion. The pharmacokinetics of fexofenadine hydrochloride in seasonal allergic rhinitis patients were similar to those in healthy subjects. Peak fexofenadine plasma concentrations were similar between adolescent (12-16 years of age) and adult patients. Fexotenadine is 60% to 70% bound to plasma proteins, primarily albumin and a1-acid glycoprotein.

Pseudoephedrine has been shown to have a mean elimination half-life of 4-6 hours, which is dependent on urine pH. The elimination half-life is decreased at urine pH lower than 6 and may be increased at urine pH higher than 8.

The bioavailability of fexofenadine hydrochloride and pseudoephedrine hydrochloride from TELFAST D Extended Release Tablets is similar to that achieved with separate administration of the components. Co-administration of fexofenadine and pseudoephedrine does not significantly affect the bioavailability of either component.

Fexofenadine hydrochloride was rapidly absorbed following sine dose administration of the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride table with median time to mean maximum fexofenadine plasma concentration of 191 ng/mL occurring 2 hours postdose. Pseudoephedrine hydrochloride produced a mean single dose pseudoephedrine peak plasma concentration of 206 ng/mL, which occurred 6 hours postdose. Following multiple dosing to steady state, a fexofenadine peak concentration of 255 ng/mL was observed 2 hours postdose. Following multiple dosing to steady state, a pseudoehedrine peak concentration of 411 ng/mL was observed 5 hours postdose.

Co-administration of TELFAST D with a high fat meal decreased fexofenadine plasma concentrations Cmax (-46%) and AUC (-42).Time to maximum concentration (Tmax) was delayed by 50%. The rate or extent of pseudoephedrine absorption was not affected by food. It is recommended that the administration of TELFAST D with food should be avoided. (See DOSAGE AND ADMINISTRATION).

Special Populations
Special population pharmaco kinetics (for renal and hepatic impairment and age), obtained after a single dose of 80 mg fexofenadine hydrochloride, were compared to those from normal subjects in a separate study of similar design. While subject weights were relatively uniform between studies, these special population patients were substantially older than the healthy, young volunteers. Thus, an age effect may be confounding the pharmacokinetic differences observed in some of the special populations.

Effect of Age. In older subjects (> 65 years old), peak plasma levels of fexofenadine were 99% greater than those observed in younger subjects (<65 years old). Mean elimination half-lives were similar to those observed in younger subjects.

Renally Impaired. In patients 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 normal volunteers. Peak plasma levels in patients on dialysis (creatinine clearance <10 mL/min) were 82% greater and half-life was 31% longer than observed in normal volunteers.

About 55-75% of an administered dose of pseudoephedrine hydrochloride is excreted unchanged in the urine; the remainder is apparently metabolized in the liver. Therefore, pseudoephedrine may accumulate in patients with renal insufficiency.

Based on increases in bioavailability and half-life of fexofenadine hydrochloride and pseudoephedrine hydrochloride, a dose of one tablet once daily is recommended as the starting dose in patients with decreased renal function (see DOSAGE AND ADMINISTRATION).

Hepatically. Impaired. The pharmacokinetics of fexofenadine hydrochloride in patients with hepatic disease did not differ substantially from that observed in healthy subjects. The effect on pseudoephedrine pharmacokinetics is unknown.

Effect of Gender. Across several trials no clinically significant gender related differences were observed in the pharmacokinetics of fexofenadine hydrochloride.

Wheal and Flare. Human histamine skin wheal and flare studies following single and twice daily doses of 20 mg and 40 mg fexofenadine
hydrochloride demonstrated that the drug exhibits an antihistamine effect by 1 hour, achieves maximum effect at 2-3 hours, and an effect is still seen at 12 hours. There was no evidence of tolerance to these effects after 28 days of dosing. The clinical significance of these observations is not known.

Effects on QTc. In dogs, (10 mg/-kg/day, orally for 5 days) and rabbits (10 mg/kg, intravenously over one hour) fexofenadine hydrochloride did not prolong QTc at plasma concentrations that were at least 28 and 63 times, respectively, the therapeutic plasma concentrations in man (based on a 60 mg twice daily fexofenadine hydrochloride dose). No effect was observed on calcium channel current, delayed K+ channel current, or action potential duration in guinea pig myocytes, Na+ current in rat neonatal myocytes, or on the delayed rectifier K+ channel cloned from human heart at concentrations up to 1 x 10-5 M of fexofenadine. This concentration was at least 32 times the therapeutic plasma concentration in man based on 60 mg twice daily fexofenadine hydrochloride dose).

No statistically significant increase in mean QTc interval compared to placebo was observed in 714 seasonal allergic rhinitis patients given fexofenadine hydrochloride capsules in doses of 60 mg to 240 mg twice daily for two weeks or in 40 healthy volunteers given fexofenadine hydrochloride as an oral solution at doses up to 400 mg twice daily for 6 days.

A one year study designed to evaluate safety and tolerability of 240 mg of fexofenadine hydrochloride (n=240) compared to placebo (n= 237) in healthy subjects, did not reveal a statistical) significant increase in the mean QTc interval for the fexofenadine hydrochloride treated group when evaluated pre-treatment and after 1,2,3,6,9 and 12 months of treatment.

Administration of the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride combination tablet for approximately 2 weeks to 213 patients with seasonal allergic rhinitis demonstrated no statistically significant increase in the mean QTc interval compared to fexofenadine hydro-chloride administered alone (60 mg twice daily, n=215), or compared to pseudoephedrine hydrochloride (120 mg twice daily, n=215) administered alone.

Clinical Studies
In a 2 week, multicenter, randomized doubleblind, active controlled trial in patients 12-65 years of age with seasonal allergic rhinitis due to ragweed allergy (n=651), the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride combination tablet administered twice daily significantly reduced 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-controlled trials in patients 12-68 years of age with seasonal aIlergic rhinitis (n=1634), fexofenadine hydrochloride 60 mg twice daily significantly reduced total symptom scores (the sum of the individual scores for sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo. Statistically significant reductions in symptom scores were observed following the first 60 mg dose, with the effect maintained throughout the 12 hour interval. In general, there was no additional reduction in total symptom scores with higher doses of fexofenadine hydrochloride up to 240 mg twice daily. Although the number of subjects in some of the subgroups was small, there were no significant differences in the effect of the fexofenadine hydrochloride across subgroups of patients defined by gender, age and race. Onset of action for reduction in total symptom scores, excluding nasal congestion, was observed at 60 minutes compared to placebo following a single 60 mg fexofenadine hydrochloride dose administered to patients with seasonal allergic rhinitis who were exposed to rag-weed pollen in an environmental exposure unit.

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