DRUG INTERACTIONS
Fexofenadine hydrochloride and pseudoephedrine hydrochloride do not influence the pharmacokinetics of each other when administered concomitantly.
Fexofenadine has been shown to exhibit minimal (ca. 5%) metabolism. However, co-administration of fexofenadine with ketoconazole and erythromycin led to increased plasma levels of fexofenadine. Fexofenadine had no effect on the pharmacokinetics of erythromycin and ketoconazole. In two separate studies, fexofenadine HCl 120 mg BID (twice the recommended dose) was co-administered with erythromycin 500 mg every 8 hours or ketoconazole 400 mg once daily under steady-state conditions to normal, healthy volunteers (n=24, each study). No differences in adverse events or QTc interval were observed when subjects were administered fexofenadine HCl alone or in combination with erythromycin or ketoconazole. The findings of these studies are summarized in the following table:
Effects on Steady-State Fexofenadine Pharmacokinetics
After 7 Days of Co-Administration with Fexofenadine
Hydrochloride 120 mg Every 12 Hours
(twice recommended dose) in Normal Volunteers (n=24)
Concomitant
Drug
|
Cmax,SS
(Peak plasma
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 in plasma levels were within the range of plasma levels achieved in adequate and well-controlled clinical trials.
The mechanism of these interactions has been evaluated in in vitro, in situ and in vivo animal models. These studies indicate that ketoconazole or erythromycin co-administration enhances fexofenadine gastrointestinal absorption. In vivo animal studies also suggest that in addition to enhancing absorption, ketoconazole decreases fexofenadine gastrointestinal secretion, while erythromycin may also decrease biliary excretion.
ALLEGRA-D tablets (pseudoephedrine component) are contraindicated in patients taking monoamine oxidase inhibitors and for 14 days after stopping use of an MAO inhibitor. Concomitant use with antihypertensive drugs which interfere with sympathetic activity (eg, methyldopa, mecamylamine, and reserpine) may reduce their antihypertensive effects. Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis.
Care should be taken in the administration of ALLEGRA-D concomitantly with other sympathomimetic amines because combined effects on the cardiovascular system may be harmful to the patient (see WARNINGS).
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OVERDOSAGE
Most reports of fexofenadine hydrochloride overdose contain limited information. However, dizziness, drowsiness, and dry mouth have been reported. For the pseudoephedrine hydrochloride component of ALLEGRA-D, information on acute overdose is limited to the marketing history of pseudoephedrine hydrochloride. Single doses of fexofenadine hydrochloride up to 800 mg (6 normal volunteers at this dose level), and doses up to 690 mg twice daily for one month (3 normal volunteers at this dose level), were administered without the development of clinically significant adverse events.
In large doses, sympathomimetics may give rise to giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, difficulty in micturition, muscular weakness and tenseness, anxiety, restlessness, and insomnia. Many patients can present a toxic psychosis with delusions and hallucinations. Some may develop cardiac arrhythmias, circulatory collapse, convulsions, coma, and respiratory failure.
In the event of overdose, consider standard measures to remove any unabsorbed drug. Symptomatic and supportive treatment is recommended. Hemodialysis did not effectively remove fexofenadine from blood (up to 1.7% removed) following terfenadine administration.
The effect of hemodialysis on the removal of pseudoephedrine is unknown.
No deaths occurred in mature mice and rats at oral doses of fexofenadine hydrochloride up to 5000 mg/kg (approximately 170 and 340 times, respectively, the maximum recommended daily oral dose in adults on a mg/m2 basis.) The median oral lethal dose in newborn rats was 438 mg/kg (approximately 30 times the maximum recommended daily oral dose in adults on a mg/m2 basis). In dogs, no evidence of toxicity was observed at oral doses up to 2000 mg/kg (approximately 450 times the maximum recommended human daily oral dose in adults on a mg/m2 basis). The oral median lethal dose of pseudoephedrine hydrochloride in rats was 1674 mg/kg (approximately 55 times the maximum recommended daily oral dose in adults on a mg/m2 basis).
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CONTRAINDICATIONS
ALLEGRA-D is contraindicated in patients with known hypersensitivity to any of its ingredients.
Due to its pseudoephedrine component, ALLEGRA-D is contraindicated in patients with narrow-angle glaucoma or urinary retention, and in patients receiving monoamine oxidase (MAO) inhibitor therapy or within fourteen (14) days of stopping such 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 hypersensitivity or idiosyncrasy to its components, to adrenergic agents, or to other drugs of similar chemical structures. Manifestations of patient idiosyncrasy to adrenergic agents include: insomnia, dizziness, weakness, tremor, or arrhythmias.
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