Special Populations

A single dose pharmacokinetic study showed that the elimination half- lives of acrivastine, the propionic acid metabolite of acrivastine, and pseudoephedrine were prolonged in patients with chronic renal insufficiency. Compared to normal volunteers, the elimination half-life of acrivastine was about 50% increased in patients with mild renal insufficiency (creatinine clearance = 26 to 48 mL/min) and was increased by about 130% in patients with moderate (creatinine clearance = 12 to 17 mL/min) or severe (creatinine clearance 6 to 10 mL/min) renal insufficiency. Oral clearance of acrivastine was diminished by the same magnitude as the half-life was prolonged in each of the three renally impaired groups. The elimination half-life of the propionic acid metabolite of acrivastine was about 140% increased in patients with mild renal insufficiency and about 5 times increased in patients with moderate or severe renal insufficiency.

Compared to normal volunteers, the elimination half-life of pseudoephedrine was about 3 times increased in patients with mild renal insufficiency, about 7 times increased in patients with moderate renal insufficiency, and about 10 times increased in patients with severe renal insufficiency. Oral clearance of pseudoephedrine was diminished by about the same magnitude as the half-life was prolonged in each of the three renally impaired groups (see PRECAUTIONS: Use in Patients with Diminished Renal Function).

The total body load removed by dialysis is approximately 20%, 27%, and 38% for acrivastine, the propionic acid metabolite of acrivastine, and pseudoephedrine, respectively, and therefore, a supplemental dose after a dialysis session is not required.

Based on a multiple dose cross study comparison, the apparent volume of distribution for acrivastine was 44% lower in elderly (n= 36, 65-75 yr) than in young volunteers (n= 16, 19-33 yr). This difference could be attributed to the decrease in total body water that occurs with aging. Despite this difference, no appreciable differences in plasma acrivastine concentrations were seen in the elderly compared to the young, and no appreciable accumulation of acrivastine occurred in plasma at steady-state. The elimination half-life for pseudoephedrine was 18% longer in elderly (7.9 hours) than in younger subjects (6.7 hours), presumably due to the decline in average renal function that occurs with aging. Despite this difference, clearance of pseudoephedrine was not appreciably different in elderly and younger subjects. Elderly patients should therefore be given the same dosage as younger patients. SEMPREX-D Capsules are not recommended, however, in patients with renal impairment (see PRECAUTIONS: Use in Patients with Diminished Renal Function).

The effect of age and sex on the pharmacokinetic parameters of acrivastine and pseudoephedrine was determined in 93 healthy volunteers who participated in various studies. All of the 93 volunteers were Caucasian (81 males and 12 females); 57 were between the ages of 18 and 38 years and 36 were between the ages of 65 and 75 years. There were no age- or sex- related differences in the pharmacokinetic parameters of either acrivastine or pseudoephedrine. The effect of race on acrivastine and pseudoephedrine pharmacokinetics was examined by screening data obtained from 1035 patients, age 12 to 71 years, who participated in the eight safety and efficacy studies. No race-related differences were observed in the pharmacokinetics of either acrivastine or pseudoephedrine.

Clinical Studies

In healthy volunteers, histamine-induced wheal and flare areas were significantly reduced relative to placebo at 30 minutes after administration of a single dose of acrivastine 8 mg. Maximum reductions of wheal and flare occurred by 1 to 2 hours and significant reductions relative to placebo persisted for up to 6 hours after a single oral dose of acrivastine 8 mg. No additional reductions of wheal and flare were observed following single doses of acrivastine up to 24 mg. The exact correlation between responses on skin testing and clinical efficacy is not established.

Five randomized, placebo- and/or active- controlled trials compared SEMPREX-D with its acrivastine and pseudoephedrine components for the symptomatic relief of seasonal allergic rhinitis. In these studies, 696 patients received four daily doses of acrivastine 8 mg plus pseudoephedrine hydrochloride 60 mg (i.e., SEMPREX-D Capsules or bioequivalent formulations administered concurrently) or the same doses of the components for 14 days. The combination reduced the intensity of sneezing, rhinorrhea, pruritus, and lacrimation more than pseudoephedrine and reduced the intensity of nasal congestion more than acrivastine, demonstrating a contribution of each of the components. The onset of antihistaminic and nasal decongestant actions occurred within one or two hours after the first dose of SEMPREX-D Capsules. Somnolence occurred in about 12% of patients given SEMPREX-D compared with about 6% on placebo.

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