Allegra

Fexofenadine+Pseudoephedrine: Fexofenadine was rapidly absorbed following multiple dose administration of the 60 mg fexofenadine/120 mg pseudoephedrine caplet to healthy volunteers with a mean peak fexofenadine plasma concentration 233 ng/mL, which occurred 2.1 hours postdose. Pseudoephedrine, in the same study, produced a mean peak pseudoephedrine plasma concentration of 405 ng/mL which occurred 4.8 hours postdose.

Coadministration of Allegra-D with a high fat meal decreased fexofenadine bioavailability; however, the rate or extent of pseudoephedrine absorption was not affected. Allegra-D should be taken on an empty stomach.

Fexofenadine: Fexofenadine is rapidly absorbed following oral administration. The single and multiple dose pharmacokinetics of fexofenadine were linear from 20 mg to 120 mg doses. T_max occurs at approximately 2.6 hours and C_max is approximately 209 ng/mL following oral administration of a single 60 mg dose.

Following a single 60 mg oral dose, 80% of the total fexofenadine dose was recovered in the feces and 11% was recovered in the urine.

Following multiple dosing, fexofenadine has an apparent elimination half-life of 11 to 16 hours. Steady-state pharmacokinetic parameters following 60 mg b.i.d. dosing are: AUC_{ss (0-12h)}=1 367 ng/mL·h, Cmax=299 ng/mL, C_min=29 ng/mL, t_max=1 h.

The pharmacokinetics of fexofenadine in seasonal allergic rhinitis patients are similar to that of otherwise healthy subjects. Peak fexofenadine plasma concentrations were similar between adolescent (12 to 16 years of age) and adult patients.

Pseudoephedrine: Pseudoephedrine has been shown to have a mean elimination half-life of 4 to 8 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. About 43 to 96% of an administered dose is excreted unchanged in the urine; the remainder is apparently metabolized in the liver.

Special Populations: There are no data available on special populations following the administration of Allegra-D. The following presentation is related to the pharmacokinetics in special populations following a single 80 mg oral dose of fexofenadine. The pharmacokinetics were compared to those from normal subjects in a separate study of similar design. While subjects' weights were relatively uniform between the studies, the special population patients were older than the healthy, young volunteers. Thus, an age effect may be confounding the pharmacokinetic differences observed.

Renal Impairment: Following a single 80 mg oral dose, renal clearance is decreased to 68, 15 and 3% of the control value (3.63 L/h) in patients with mild to moderate impairment (creatinine clearance 41 to 80 mL/min; n=9), moderate to severe impairment (creatinine clearance 11 to 40 mL/min; n=10) and dialysis patients (creatinine clearance <10 mL/min; n=10). The corresponding AUC_0-∞ and C_max were increased by 80, 154 and 88%, respectively (control value=1 788.1 ng/mL·h), and by 58, 78 and 54%, respectively (control value=248.7 ng/mL). The half-life increased from 13.7 hours to 22.8, 24.8 and 18.9 hours, respectively.

Hepatic Impairment: The pharmacokinetics of fexofenadine in 14 patients with hepatic disease (moderate, n=9; moderate to severe, n=5), did not differ substantially from that observed in healthy subjects. The lack of effect may be explained by the fact that none of the patients investigated suffered from complete biliary obstruction, as biliary excretion is one of the major elimination pathways for fexofenadine.

Effect of Age: The pharmacokinetics of fexofenadine in healthy elderly individuals (>65 years old, n=20) were different from those observed in healthy younger individuals following a single oral dose of 80 mg fexofenadine. Mean AUC was 63% higher (control value=1 788 ng/mL.h), oral clearance 30% lower (control value= 48 L/h), renal clearance 24% less (control value=3.6 L/h), C_max 68% higher (control value=248.7 ng/mL) and half-life 10% longer (15.2 h).

Effect of Sex: The steady-state AUC and C_max values in female subjects (n=20) were 33% and 46% higher, respectively, than those observed in male subjects (n=20). Renal clearance was equivalent. There was no indication of any difference in safety or efficacy.

Fexofenadine has no effect on the pharmacokinetics of erythromycin and ketoconazole. The coadministration of fexofenadine with erythromycin or ketoconazole resulted in no significant increases in QT_c. No differences in adverse effects were reported whether this agent was administered alone or in combination with erythromycin or ketoconazole.

Since fexofenadine does not undergo hepatic biotransformation, it is unlikely to interact with drugs that rely upon hepatic metabolism.

The administration of a single 20 mL dose of Maalox suspension followed 15 minutes later by a single oral dose of 120 mg fexofenadine resulted in a significant reduction in fexofenadine bioavailability (41% reduction in AUC_(0-30h); 43% reduction in C_max). This interaction has been explained on the basis that up to 27.8% of fexofenadine is physically bound to Maalox in the stomach at pH of 4 or greater (see Information for the Patient).

Concomitant use of pseudoephedrine with MAOIs and use within 14 days after stopping an MAOI are contraindicated.

Concomitant use of pseudoephedrine with antihypertensive drugs which interfere with sympathetic activity may reduce their antihypertensive effects.

Concomitant use of pseudoephedrine with sympathomimetic agents may have additive cardiovascular effects.

The elderly are more likely to have adverse reactions to sympathomimetic amines.

Allegra-D is not recommended for nursing women unless the potential benefit to the patient outweighs the potential risk to the infant. Following administration of terfenadine to nursing mothers, fexofenadine crosses into human breast milk and pseudoephedrine administered alone, distributes into breast milk.

There are no data available to indicate that abuse or dependency occurs with Allegra-D.

Safety and effectiveness of Allegra-D have not been established in children under 12 years of age.

Allegra-D should be used with caution in patients with hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, renal impairment, prostatic hypertrophy, or hyperreactivity to ephedrine.

Sympathomimetics should be used with caution in patients receiving digitalis.

Sympathomimetics may cause CNS stimulation and convulsions or cardiovascular collapse with accompanying hypotension.

There are no adequate and well controlled studies in pregnant women. Allegra-D should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Patients with decreased renal function should be given a lower initial dose, 1 caplet/day, due to the reduced elimination of fexofenadine and pseudoephedrine.

Allegra-D should be discontinued approximately 3 days prior to skin testing procedures since antihistamines may prevent or diminish otherwise positive reactions to dermal reactivity indications.

abdominal pain, constipation, dyspepsia, diarrhea, dry throat, dry lips, aphthous stomatitis.

bilirubinemia, AST increased, ALT increased.

eosinophilia, leukocytosis, neutrophilia.

myopathy, knee pain, tendon rupture.

drowsiness, psychomotor hyperactivity, somnolence, tremor.

Statistically significant mean changes from baseline to endstudy were observed for ALT, albumin, hemoglobin, RBC, WBC, chloride and total cholesterol. However, these changes were not considered clinically significant.

taste perversion, taste metallic.

Pseudoephedrine has also been associated with other adverse effects such as anorexia, fear, anxiety, tenseness, weakness, pressor activity/hypertension, tremor, hallucinations, seizures, pallor, respiratory difficulty, difficulty in micturition, cardiac arrhythmia and cardiovascular collapse. Pseudoephedrine may produce mild CNS stimulation.

In rare cases, rash, urticaria, pruritus, and hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnea, flushing and systemic anaphylaxis, fatigue, chills, lassitude, neck pain, thoracic cage pain.

hyperkalemia, hyperlipemia, hypoglycemia, hyperglycemia.

Clinical adverse events occurring in less than 1% of patients treated with Allegra-D in clinical trials which have been reported rarely during postmarketing surveillance, are listed below by body system:

epistaxis, hemoptysis, nasal dryness, nasal irritation, pharyngitis, sinusitis, wheezing.

rash, urticaria, pruritus, acne, cold sweat, seborrhea.

dry eyes.

restlessness, irritability, anorexia, increased energy, depersonalization, sleep disorder or paroniria.

AV block, atrial arrhythmia, tachycardia, heart murmur, syncope.

Fexofenadine: Most reports of fexofenadine overdose contain limited information. However, dizziness, drowsiness, and dry mouth have been reported. Single doses up to 800 mg and doses up to 690 mg b.i.d. for 1 month or 240 mg once daily for 1 year were studied in healthy subjects without the development of clinically significant adverse events as compared to placebo. The maximum tolerated dose of fexofenadine was not established.

Pseudoephedrine: Serious effects associated with pseudoephedrine overdosage include respiratory difficulty, convulsions, arrhythmias, hypertension and cardiovascular collapse.

Manifestations: These may vary from CNS depression (sedation, apnea, diminished mental alertness, cyanosis, coma, cardiovascular collapse) to stimulation (insomnia, hallucination, tremors or convulsions) to death. Other signs and symptoms may be euphoria, excitement, tachycardia, palpitations, thirst, perspiration, nausea, dizziness, tinnitus, ataxia, blurred vision and hypertension or hypotension. Stimulation is particularly likely in children, as are atropine-like signs and symptoms (dry mouth; fixed, dilated pupils; flushing; hyperthermia; and gastrointestinal symptoms).

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 overdosage, treatment which should be started immediately, is symptomatic and supportive. Discontinuation of use, gastric lavage or induction of emesis (except in patients with impaired consciousness) and support of vital functions are advised.

The patient should be induced to vomit, even if emesis has occurred spontaneously. Pharmacologically-induced vomiting by the administration of ipecac syrup is a preferred method. However, vomiting should not be induced in patients with impaired consciousness. The action of ipecac is facilitated by physical activity and by the administration of 240 to 360 mL of water. If emesis does not occur within 15 minutes, the dose of ipecac should be repeated. Precautions against aspiration must be taken, especially in children. Following emesis, adsorption of any drugs remaining in the stomach may be attempted by the administration of activated charcoal as a slurry with water. If vomiting is unsuccessful, or contraindicated, gastric lavage should be performed. Physiologic saline solution is the lavage solution of choice, particularly in children. In adults, tap water can be used; however, as much as possible of the amount administered should be removed before the next instillation. Saline cathartics draw water into the bowel by osmosis and therefore may be valuable for their action in rapid dilution of bowel content.

Fexofenadine is not effectively cleared by hemodialysis from the blood. The effect of hemodialysis on pseudoephedrine is unknown.

Excretion of pseudoephedrine is increased by lowering the pH of the urine.

After emergency treatment, the patient should continue to be medically monitored.

Stimulants (analeptic agents) should not be used. Vasopressors may be used to treat hypotension. Short-acting barbiturates, diazepam or paraldehyde may be administered to control seizures. Hyperpyrexia, especially in children, may require treatment with tepid water sponge baths or hypothermic blanket. Apnea is treated with ventilatory support.