Professional Information
Fexofenadine and Pseudoephedrine (Systemic)
VA CLASSIFICATION
Primary: RE501
Commonly used brand name(s): Allegra-D.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antihistaminic (H 1-receptor)–decongestant—
Indications
Accepted
Rhinitis, seasonal allergic (treatment)—Fexofenadine and pseudoephedrine combination is indicated for symptomatic relief of seasonal allergic rhinitis (including sneezing; rhinorrhea; itchy nose, palate, and/or throat; itchy, watery, red eyes; and nasal congestion) in adults and children 12 years of age and older when both antihistaminic and decongestant effects are desired {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Chemical group—
Fexofenadine hydrochloride:
Piperidine derivative {01}. Fexofenadine is the major active metabolite of terfenadine {01}.
Molecular weight—
Fexofenadine hydrochloride:
538.13 {01}.
Pseudoephedrine hydrochloride:
201.7 {01}.
Solubility
Fexofenadine hydrochloride:
Freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane {01}.
Pseudoephedrine hydrochloride:
Very soluble in water, freely soluble in alcohol, and sparingly soluble in chloroform {01}.
Mechanism of action/Effect:
Fexofenadine:
A selective peripheral H 1-receptor antagonist that has been found to inhibit antigen-induced bronchospasm in sensitized guinea pigs and histamine release from peritoneal mast cells in rats {01}.
Pseudoephedrine:
A sympathomimetic amine that has a decongestant effect on the nasal mucosa. Its peripheral effects are similar to those of ephedrine and its central effects are similar to, but less intense than, those of amphetamines. {01}
Other actions/effects:
Fexofenadine:
Animal studies have not found that fexofenadine has anticholinergic or alpha 1-adrenergic receptor activity, and no sedative or other central nervous system (CNS) effects have been observed {01}.
Pseudoephedrine has the potential for excitatory side effects, but has little or no pressor effect in normotensive adults {01}.
Absorption:
Bioavailability of fexofenadine and pseudoephedrine from the combination formulation is similar to that observed with administration as single agents {01}. Coadministration with a high-fat meal has been found to decrease peak fexofenadine plasma concentrations and area under the curve (AUC) by 46% and 42%, respectively, and to delay the time to peak plasma concentration by 50% {01}. The rate and extent of pseudoephedrine absorption have not been found to be affected by food {01}.
Fexofenadine:
Rapidly absorbed in combination form with pseudoephedrine {01}. Absolute bioavailability has not been established {01}.
Distribution:
Fexofenadine has not been found to cross the blood-brain barrier {01}.
Protein binding:
Fexofenadine:
Moderate (60 to 70%), primarily to albumin and alpha 1-acid glycoprotein {01}.
Biotransformation:
Fexofenadine:
Hepatic; approximately 5% of the total dose is metabolized {01}.
Pseudoephedrine:
Hepatic, 25 to 45% {01}.
Half-life:
Elimination:
Fexofenadine—
Mean, 14.4 hours following administration to steady-state as a single agent to healthy volunteers {01}.
Pseudoephedrine—
Mean, 4 to 6 hours, depending on urine pH (elimination half-life is reduced at a pH less than 6 and increased at a pH above 8) {01}.
Onset of action:
Fexofenadine (antihistaminic effect):
1 hour {01}.
Time to peak concentration:
Plasma:
Fexofenadine—
2 hours following single or multiple doses {01}.
Pseudoephedrine—
6 hours following a single dose; 5 hours following multiple doses to steady-state {01}.
Peak plasma concentration
Fexofenadine:
191 nanograms per mL following administration of a single dose of the combination of 60 mg of fexofenadine hydrochloride and 120 mg of pseudoephedrine hydrochloride; 225 nanograms per mL following multiple dose administration to steady-state {01}.
Peak plasma concentrations have been found to be increased by 87% and mean elimination half-life increased by 59% in patients with mild renal function impairment (creatinine clearance 41 to 80 mL per minute [mL/min]), compared with those in normal volunteers. In patients with severe renal function impairment (creatinine clearance 11 to 40 mL/min), peak plasma concentrations were increased by 111% and mean elimination half-life increased by 72%. In patients on dialysis (creatinine clearance 10 mL/min or less), peak plasma concentrations and half-life were increased by 82% and 31%, respectively. {01}
Pseudoephedrine:
206 nanograms per mL following administration of a single dose of the combination of 60 mg of fexofenadine hydrochloride and 120 mg of pseudoephedrine hydrochloride; 411 nanograms per mL following multiple dose administration to steady-state {01}.
Time to peak effect:
Fexofenadine (antihistaminic effect):
2 to 3 hours {01}.
Duration of action:
Fexofenadine (antihistaminic effect):
At least 12 hours {01}.
Elimination:
Fexofenadine—
Fecal, 80% {01}. Because absolute bioavailability has not been established, it is not known if this component is unabsorbed drug or the result of biliary excretion {01}.
Renal, 11% {01}.
Pseudoephedrine—
Renal, 55 to 75% unchanged {01}.
In dialysis—
Fexofenadine is not effectively removed by hemodialysis {01}. It is not known whether pseudoephedrine is removable by hemodialysis {01}.
Note: Fexofenadine exhibits linear pharmacokinetics for oral doses of up to 120 mg administered twice a day. {01}
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to other adrenergic agents may also be sensitive to pseudoephedrine {01}.
Carcinogenicity
No animal or in vitro studies with the combination of fexofenadine and pseudoephedrine have been done {01}.
Studies in mice and rats at oral daily doses of terfenadine of up to 150 mg per kg of body weight (mg/kg) (producing adequate fexofenadine exposure [area under the curve (AUC)], or up to three times the human AUC at the maximum recommended daily oral dose in adults) for 18 and 24 months, respectively, found no evidence of carcinogenicity {01}.
Studies in rats and mice with ephedrine sulfate (an agent structurally related to and with similar pharmacologic properties as pseudoephedrine) at oral doses of up to 10 and 27 mg/kg, respectively (approximately one third and one half, respectively, the maximum recommended daily oral dose of pseudoephedrine hydrochloride in adults on a mg per square meter of body surface area basis) found no evidence of carcinogenicity {01}.
Mutagenicity
Fexofenadine was not found to be mutagenic in in vitro (bacterial reverse mutation, CHO/HGPRT forward mutation, and rat lymphocyte chromosomal aberration assays) or in vivo (mouse bone marrow micronucleus assay) tests {01}.
Pregnancy/Reproduction
Fertility—
Studies in rats given oral doses of terfenadine of up to 300 mg/kg showed no effect on male or female fertility. {01} However, a reduction in implants was observed at an oral dose of 150 mg/kg per day, and both a reduction in implants and postimplantation losses were reported at 300 mg/kg. {01} (Oral doses of 150 and 300 mg/kg of terfenadine produced fexofenadine AUC values of approximately three and four times, respectively, the human AUC at the maximum recommended daily oral dose in adults.) {01}
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
Studies in rats and rabbits given oral doses of terfenadine of up to 300 mg/kg (producing fexofenadine AUC values in rats and rabbits of approximately 4 and 30 times, respectively, the human AUC at the maximum recommended daily oral dose in adults) found no evidence of teratogenicity. However, studies in rats given an oral combination of terfenadine and pseudoephedrine at a dose of 150/300 mg/kg found reduced fetal weight and delayed ossification with a finding of wavy ribs. (The terfenadine dose produced a fexofenadine AUC value of approximately three times the human AUC at the maximum recommended daily oral dose in adults. The dose of pseudoephedrine was approximately 10 times the maximum recommended daily oral dose in adults on a mg per square meter of body surface area basis.) {01}
Dose-related decreases in pup weight gain and survival occurred in rats at oral doses of 150 mg/kg of terfenadine (producing fexofenadine AUC values of approximately three times the human AUC at the maximum recommended daily oral dose in adults). Studies in rabbits given an oral combination of terfenadine and pseudoephedrine at a dose of 100/200 mg/kg found reduced fetal weight. (By extrapolation, the terfenadine dose produced a fexofenadine AUC value of approximately 10 times the human AUC at the maximum recommended daily oral dose in adults and the dose of pseudoephedrine was approximately 15 times the maximum recommended daily oral dose in adults on a mg per square meter of body surface area basis.) {01}
Risk-benefit should be considered before using this medication during pregnancy {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether fexofenadine is distributed into breast milk. Pseudoephedrine is distributed into breast milk in concentrations that are consistently higher than those in plasma (approximately two to three times higher in breast milk than the plasma AUC); the fraction of pseudoephedrine distributed into breast milk is estimated to be 0.4 to 0.7%. Risk-benefit should be considered before use of the combination medication in women who are breast-feeding. {01}
Pediatrics
Safety and efficacy of fexofenadine and pseudoephedrine in children younger than 12 years of age have not been established {01}.
Geriatrics
Appropriate studies on the relationship of age to the effects of fexofenadine and pseudoephedrine have not been performed in the geriatric population. However, peak plasma concentrations of fexofenadine have been observed to be 99% greater in patients 65 years of age and older, compared with those in younger subjects; no differences in elimination half-life were observed. Elderly patients are more likely to have adverse reactions to sympathomimetic amines. In general, cautious dosing is recommended for the elderly (beginning at the low end of the dosage range), keeping in mind the possibility that they may have decreased hepatic, renal, or cardiac function along with other concomitant diseases or use of other medications. Elderly patients are more likely to have age-related renal function impairment, which requires adjustment of dosage. {01}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Antihypertensives that interfere with symphathomimetic activity{01} , such as:
Mecamylamine{01}
Methyldopa{01}
Reserpine (concurrent administration with pseudoephedrine may lead to reduced antihypertensive effects {01})
Digitalis glycosides{01} (concurrent administration with pseudoephedrine can result in increased ectopic pacemaker activity {01})
Erythromycin{01} or
Ketoconazole{01} (concurrent administration with fexofenadine has been found to increase plasma fexofenadine concentrations; however, no differences in adverse effects or increased QTc intervals were seen {01})
» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline{01} (pseudoephedrine should not be administered during or within 14 days following administration of MAO inhibitors {01})
Sympathomimetics, other{01} (concurrent use may increase the cardiovascular effects of either the other sympathomimetics or pseudoephedrine and the potential for side effects {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
Sensitivity to fexofenadine or pseudoephedrine or other sympathomimetics{01}
For pseudoephedrine:
» Coronary artery disease, severe{01} or
» Hypertension, severe{01} (condition may be exacerbated due to drug-induced cardiovascular effects)
Diabetes mellitus{01} (may lead to increased blood glucose concentrations)
» Glaucoma, narrow-angle{01} or
Increased intraocular pressure (condition may be exacerbated)
Hyperthyroidism{01} (symptoms may be exacerbated)
Ischemic heart disease{01} (condition may be exacerbated due to drug-induced cardiovascular effects)
Prostatic hypertrophy{01} (urinary retention may be precipitated)
» Renal function impairment{01} (based upon the increases in bioavailability and half-life of fexofenadine and pseudoephedrine, once-daily administration is recommended initially in patients with impaired renal function {01})
» Urinary retention{01} (condition may be exacerbated)
Side/Adverse Effects
Note: Pseudoephedrine alone may cause mild CNS stimulation in hypersensitive patients, including nervousness, excitability, restlessness, dizziness, weakness, or insomnia. Other effects include headache, drowsiness, tachycardia, palpitation, pressor activity, and cardiac arrhythmias. {01} Dizziness and insomnia may be manifestations of patient idiosyncrasy to adrenergic agents; other manifestations may include weakness, tremor, or cardiac arrhythmias {01}.
Possible adverse effects of sympathomimetic amines include CNS stimulation with convulsions or cardiovascular collapse and accompanying hypotension. Sympathomimetic medications have been associated with fear, anxiety, tremor, hallucinations, seizures, pallor, respiratory difficulty, dysuria, and cardiovascular collapse. {01}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Insomnia{01} (trouble in sleeping)
Incidence less frequent
Dizziness{01}
nervousness{01}
palpitations{01} (irregular heartbeat)
upper respiratory infection{01} (cough; sore throat)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Headache{01}
nausea{01}
Incidence less frequent
Abdominal or stomach pain{01}
agitation{01}
anxiety{01}
back pain{01}
dry mouth{01}
dyspepsia{01} (heartburn)
sore throat{01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
No specific experience with combination fexofenadine/pseudoephedrine has been reported {01}.
Large doses of sympathomimetics may cause giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, difficulty in micturition, muscular weakness and tenseness, anxiety, restlessness, and insomnia. A toxic psychosis with delusions and hallucinations is common. Some patients may develop cardiac arrhythmias, circulatory collapse, convulsions, coma, and respiratory failure.
Treatment of overdose
Standard measures to remove unabsorbed medication may be considered {01}.
Hemodialysis does not effectively remove fexofenadine from blood (up to 1.7% removed); it is not known whether hemodialysis removes pseudoephedrine {01}.
Supportive care—Symptomatic and supportive treatment is recommended {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Fexofenadine and Pseudoephedrine (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to fexofenadine or pseudoephedrine
Pregnancy—In animal studies, terfenadine and pseudoephedrine caused reduced weight and delayed ossification in the offspring
Breast-feeding—Pseudoephedrine is distributed into breast milk; risk-benefit should be considered
Use in the elderly—Older patients may be more sensitive to some of the effects of pseudoephedrine; and age-related decreases in hepatic, renal, or cardiac function are a possibility and may require a dosage reduction
Other medications, especially monoamine oxidase (MAO) inhibitors
Other medical problems, especially severe coronary artery disease, severe hypertension, narrow-angle glaucoma, renal function impairment and urinary retention
Proper use of this medication
Swallowing tablet whole; not breaking or chewing tablet
Taking medication on an empty stomach
» Proper dosing
Missed dose: Taking as soon as remembered; not taking if almost time for next dose; not doubling doses
Importance of not taking more than the prescribed dose or more frequently than recommended
» Proper storage
Side/adverse effects
Signs of potential side effects, especially dizziness, insomnia, nervousness, palpitations, or upper respiratory infection
General Dosing Information
It is recommended by the manufacturer that patients stop taking the medication and check with their physician if dizziness, insomnia, or nervousness occurs {01}.
Diet/Nutrition
It is recommended by the manufacturer that the administration of fexofenadine/pseudoephedrine extended-release tablets with food be avoided {01}.
Oral Dosage Forms
FEXOFENADINE HYDROCHLORIDE AND PSEUDOEPHEDRINE HYDROCHLORIDE EXTENDED-RELEASE TABLETS
Usual adult and adolescent {01} dose
Antihistaminic-decongestant
Oral, 1 tablet twice a day {01}.
Note: In patients with reduced renal function, a starting dose of 1 tablet once a day is recommended {01}.
Usual pediatric dose
Antihistaminic-decongestant
Children younger than 12 years of age:
Safety and efficacy have not been established {01}
Children 12 years of age and over:
See Usual adult and adolescent dose {01}.
Strength(s) usually available
U.S.—
60 mg fexofenadine hydrochloride and 120 mg pseudoephedrine hydrochloride (Rx) [Allegra-D]
Note: The fexofenadine hydrochloride is in immediate-release form and the pseudoephedrine is in extended-release form {01} controlled by an insoluable wax matrix {02}.
Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F) {01}.
Auxiliary labeling:
• Take on an empty stomach.
• Swallow tablets whole.
Developed: 08/12/1998
Revised:
References
- Allegra-D package insert (Hoechst Marion Roussel—US), Rev 12/97, Rec 1/23/98.
- Manufacturer comment, 08/03/98.
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