SEMPREX D Capsule Ref.[9935] Active ingredients: Acrivastine Pseudoephedrine

SEMPREX-D Capsules should be used with caution in patients with hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, prostatic hypertrophy, stenosing peptic ulcer, or pyloroduodenal obstruction. Overdose of sympathomimetic amines may produce CNS stimulation with convulsions or cardiovascular collapse with accompanying hypotension. The elderly are more likely to have adverse reactions to sympathomimetic amines.

Information on the incidence of adverse events in clinical investigations conducted in the United States was obtained from 33 controlled and 15 uncontrolled clinical studies in which 2499 patients received acrivastine and 2631 patients received acrivastine plus pseudoephedrine hydrochloride for treatment periods ranging from one day to one year. The majority of patients in clinical trials were exposed to acrivastine or acrivastine plus pseudoephedrine for less than 90 days. Acrivastine dosage ranged from 3 to 96 mg/day; 1336 patients received dosages equal to or greater than acrivastine 24 mg/day. Acrivastine plus pseudoephedrine hydrochloride dosages ranged from acrivastine 8 to 48 mg/day plus pseudoephedrine hydrochloride 60 to 240 mg/day. A total of 2335 patients received three or four daily doses of acrivastine 8 mg plus pseudoephedrine hydrochloride 60 mg.

In controlled clinical trials, only 12 spontaneously elicited adverse events were reported with frequencies greater than 1% in the acrivastine plus pseudoephedrine hydrochloride treatment group (see Table 1).

TABLE 1. ADVERSE EVENTS REPORTED IN CLINICAL TRIALS^* (PERCENT OF PATIENTS REPORTING)^†:

* Includes all events regardless of casual relationship to treatment.
^† Includes all adverse events with a reported frequency of >1% for the acrivastine plus pseudoephedrine treatment group.
^‡ SEMPREX-D demonstrates a statistically higher frequency of events than placebo, p ≤0.05.

The nature and overall frequencies of adverse events from international clinical trials (35 studies involving approximately 1600 patients) were similar to the results obtained in the US studies.

Post-marketing clinical experience reports with acrivastine and acrivastine plus pseudoephedrine have included rare serious hypersensitivity reactions manifested by anaphylaxis, angioedema, bronchospasm, and erythema multiforme. No deaths associated with use of acrivastine or acrivastine plus pseudoephedrine have been reported.

Pseudoephedrine may cause ephedrine-like reactions such as tachycardia, palpitations, headache, dizziness, or nausea (see WARNINGS and OVERDOSAGE).

Serious skin reactions, including acute generalized exanthematous pustulosis (AGEP), have been reported with pseudoephedrine-containing products.

Use in Patients with Diminished Renal Function

Acrivastine and pseudoephedrine are excreted primarily through the kidney. Both compounds therefore accumulate in patients with impaired renal function. Due to the differential effects of renal failure on the serum half-life and clearance of acrivastine and pseudoephedrine, use of SEMPREX-D Capsules, a fixed combination product, in patients with renal impairment (creatinine clearance ≤48 mL/min) is not recommended (see OVERDOSAGE and CLINICAL PHARMACOLOGY).

Acrivastine is sedating in some patients. In controlled clinical trials, somnolence (i.e., drowsiness, sedation, sleepiness) was more common with SEMPREX-D Capsules (by an average of 6%) than with placebo (see ADVERSE EXPERIENCES).

Patients should be advised to assess their individual responses to SEMPREX-D Capsules before engaging in any activity requiring mental alertness, such as driving a motor vehicle or operating machinery. Concurrent use of SEMPREX-D Capsules with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of CNS performance and should be avoided (see PRECAUTIONS, Drug Interactions).

Patients taking SEMPREX-D Capsules should receive the following information. SEMPREX-D Capsules are prescribed to reduce symptoms associated with seasonal allergic rhinitis. Patients should be instructed to take SEMPREX-D Capsules only as prescribed and not to exceed the prescribed dose. Patients should be advised against the concurrent use of SEMPREX-D with over-the-counter antihistamines and decongestants. Patients who are or may become pregnant should be told that this product should be used in pregnancy or during lactation only if the potential benefit justifies the potential risks to the fetus or nursing infant. Due to the risk of hypertensive crisis, patients should be instructed not to take SEMPREX-D Capsules (acrivastine and pseudoephedrine hydrochloride) if they are presently taking a monoamine oxidase inhibitor or for 14 days after stopping use of an MAO inhibitor. Patients should be advised to assess their individual responses to SEMPREX-D Capsules before engaging in any activity requiring mental alertness, such as driving a car or operating machinery. Patients should be advised that the concurrent use of SEMPREX-D Capsules with alcohol and other CNS depressants may lead to additional reductions in alertness and impairment of CNS performance and should be avoided.

MAO inhibitors and beta-adrenergic agonists increase the effects of sympathomimetic amines. Concomitant use of sympathomimetic amines with MAO inhibitors can result in a hypertensive crisis (see CONTRAINDICATIONS). Because MAO inhibitors are long-acting, SEMPREX-D Capsules should not be taken with an MAO inhibitor or for 14 days after stopping use of an MAO inhibitor.

Because of their pseudoephedrine content, SEMPREX-D Capsules may reduce the antihypertensive effects of drugs that interfere with sympathetic activity. Care should be taken in the administration of SEMPREX-D Capsules concomitantly with other sympathomimetic amines because the combined effects on the cardiovascular system may be harmful to the patient.

Concomitant administration of SEMPREX-D Capsules with alcohol and other CNS depressants may result in additional reductions in alertness and impairment of CNS performance and should be avoided.

No formal drug interaction studies between SEMPREX-D Capsules and other possibly co-administered drugs have been performed.

Teratogenic Effects

No evidence of teratogenicity was seen in rats and rabbits given acrivastine 1000 and 400 mg/kg/day, respectively (5900 and 4720 mg/m²/day or 249 and 200 times the recommended human daily dose). No evidence of teratogenicity was seen in rats given a combination of acrivastine 30 mg/kg/day and pseudoephedrine 150 mg/kg/day (177 and 885 mg/m²/day or 8 and 5 times the recommended human daily dose, respectively). Similarly, no evidence of teratogenicity was observed in rabbits given acrivastine 20 mg/kg/day and pseudoephedrine 100 mg/kg/day (236 and 1180 mg/m²/day or 10 and 7 times the recommended human daily doses, respectively). There are, however, no adequate and well-controlled studies in pregnant women. Because animal teratology studies are not always predictive of human responses, SEMPREX-D Capsules should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus.

Nonteratogenic Effects

In a perinatal-postnatal study in rats, acrivastine given alone at levels up to 500 mg/kg/day (2950 mg/m²/day or 124 times the recommended human daily dose) was associated with maternal and neonatal mortality at the maximum dose level. Neonatal survival was decreased in rats given a combination of acrivastine 20 mg/kg/day and pseudoephedrine 100 mg/ kg/day (118 and 590 mg/m²/day or 5 and 3 times the human dose, respectively).

It is not known whether acrivastine is excreted in human milk; pseudoephedrine is excreted in human milk. SEMPREX-D Capsules should only be used in nursing mothers when the potential benefit justifies the potential risks to the nursing infant.

Safety and effectiveness of SEMPREX-D Capsules in pediatric patients under the age of 12 years have not been established.

Of the total number of subjects in clinical studies of SEMPREX-D, 349 were 60 years of age or older and 53 were 70 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Antihistamines, however, as a pharmaceutical class, are more likely to cause dizziness, sedation, bladder-neck obstruction, and hypotension in elderly patients. The elderly are also more likely to have adverse reactions to sympathomimetics such as pseudoephedrine (see CLINICAL PHARMACOLOGY and WARNINGS).

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to 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 monitor renal function. Use of SEMPREX-D in patients with renal impairment (creatinine clearance ≤ 48 mL/min) is not recommended (see PRECAUTIONS, Use in Patients with Diminished Renal Function).