Side Effects of Allegra D (fexofenadine and pseudoephedrine)

Allegra (fexofenadine and pseudoephedrine) is a combination of an oral, "second generation" antihistamine and a decongestant used to treat seasonal allergies in patients 2 years of age and older and chronic urticaria (hives, itching) in patients 6 months of age and older. 

Histamine is a chemical responsible for many of the signs and symptoms of allergic reactions, for example, swelling of the lining of the nose, sneezing, and itchy eyes. Histamine is released from histamine-storing cells (mast cells) and then attaches to other cells that have receptors for histamine. 

The attachment of the histamine to the receptors causes the cells to be "activated," releasing other chemicals that produce the effects that we associate with allergy (for example, sneezing). Fexofenadine blocks one type of receptor for histamine (the H1 receptor) and thus prevents activation of H1 receptor-containing cells by histamine. 

Unlike the first-generation antihistamines, fexofenadine and other second-generation antihistamines do not readily enter the brain from the blood. Therefore, they cause less drowsiness and are called non-sedating antihistamines. 

Pseudoephedrine causes blood vessels in the nasal passages to narrow (vasoconstrict). Vasoconstriction reduces nasal congestion by preventing fluid from draining from blood vessels into nasal passages. 

Common side effects of Allegra D include

• nervousness,
• restlessness,
• excitability,
• dizziness,
• headache,
• fear,
• anxiety,
• tremor,
• hallucinations, and
• convulsions (seizures).

Other important side effects of Allegra D include

• drowsiness,
• fatigue,
• nausea, and
• vomiting.

Drug interactions of Allegra D include monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine because combining pseudoephedrine with MAOIs can lead to dangerous increases in blood pressure and other serious side effects.

• Aluminum containing antacids (for example, Maalox) reduces the absorption of fexofenadine.
• Therefore, aluminum containing antacids and fexofenadine should not be administered together.
• Fruit juices (apple, orange, grapefruit) may reduce the absorption of fexofenadine, and fexofenadine should only be administered with water.

There have been associations between first trimester exposure to drugs related to pseudoephedrine and fetal malformations, though the malformations have been primarily minor. Thus, Allegra-D should be used in pregnancy only if the physician feels that the potential benefit outweighs the risks. Fexofenadine has not been adequately studied in pregnant women. 

Pseudoephedrine is excreted in breast milk. The American Academy of Pediatrics considers pseudoephedrine to be compatible with nursing. Fexofenadine has not been adequately studied in women who are breastfeeding. Consult your doctor before breastfeeding. 

Side effects of Allegra-D include stimulation of the nervous system by pseudoephedrine leading to:

• nervousness,
• restlessness,
• excitability,
• dizziness,
• headache,
• fear,
• anxiety,
• tremor, hallucinations, and
• convulsions (seizures).

Other important side effects include:

• drowsiness,
• fatigue,
• nausea, and
• vomiting.

Allegra-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR

In one clinical trial (n=651) in which 215 subjects with seasonal allergic rhinitis received the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride combination tablet twice daily for up to 2 weeks, adverse events were similar to those reported either in subjects receiving fexofenadine hydrochloride 60 mg alone (n=218 subjects) or in subjects receiving pseudoephedrine hydrochloride 120 mg alone (n=218). A placebo group was not included in this study.

The percent of subjects who withdrew prematurely because of adverse events was 3.7% for the fexofenadine hydrochloride/pseudoephedrine hydrochloride combination group, 0.5% for the fexofenadine hydrochloride group, and 4.1% for the pseudoephedrine hydrochloride group. All adverse events that were reported by greater than 1% of subjects who received the recommended daily dose of the fexofenadine hydrochloride/pseudoephedrine hydrochloride combination are listed in the following table.

Adverse Experiences Reported in One Active-Controlled Seasonal Allergic Rhinitis Clinical Trial at Rates of Greater than 1%

Many of the adverse events occurring in the fexofenadine hydrochloride/pseudoephedrine hydrochloride combination group were adverse events also reported predominately in the pseudoephedrine hydrochloride group, such as

• insomnia,
• headache,
• nausea,
• dry mouth,
• dizziness,
• agitation,
• nervousness,
• anxiety, and
• palpitation.

Fexofenadine Hydrochloride

• In placebo-controlled clinical trials, which included 2461 subjects receiving fexofenadine hydrochloride at doses of 20 mg to 240 mg twice daily, adverse events were similar in fexofenadine hydrochloride and placebo-treated subjects.
• The incidence of adverse events, including drowsiness, was not dose related and was similar across subgroups defined by age, gender, and race.
• The percent of subjects who withdrew prematurely because of adverse events was 2.2% with fexofenadine hydrochloride vs 3.3% with placebo.
• Events that have been reported during controlled clinical trials involving subjects with seasonal allergic rhinitis and chronic idiopathic urticaria at incidences less than 1% and similar to placebo and have been rarely reported during postmarketing surveillance include:
  • insomnia,
  • nervousness, and
  • sleep disorders or paroniria.
• In rare cases, rash, urticaria, pruritus and hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnea, flushing and systemic anaphylaxis have been reported.

Pseudoephedrine Hydrochloride

• Pseudoephedrine hydrochloride may cause mild CNS stimulation in hypersensitive patients.
• Nervousness, excitability, restlessness, dizziness, weakness, or insomnia may occur.
• Headache, drowsiness, tachycardia, palpitation, pressor activity, cardiac arrhythmias and ischemic colitis have been reported.
• Sympathomimetic drugs have also been associated with other untoward effects such as
  • fear,
  • anxiety,
  • tenseness,
  • tremor,
  • hallucinations,
  • seizures,
  • pallor,
  • respiratory difficulty,
  • dysuria, and
  • cardiovascular collapse.

• 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 hydrochloride with either ketoconazole or erythromycin led to increased plasma concentrations of fexofenadine.
• Fexofenadine had no effect on the pharmacokinetics of either erythromycin or ketoconazole.
• In 2 separate studies, fexofenadine hydrochloride 120 mg twice daily (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 healthy volunteers (n=24, each study).
• No differences in adverse events or QTc interval were observed when subjects were administered fexofenadine hydrochloride alone or in combination with either 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 (two times the recommended twice daily dose) in Healthy Volunteers (n=24)

• 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. This observed increase in the bioavailability of fexofenadine may be due to transport-related effects, such as p-glycoprotein.
• In vivo animal studies also suggest that in addition to enhancing absorption, ketoconazole decreases fexofenadine gastrointestinal secretion, while erythromycin may also decrease biliary excretion.
• Due to the pseudoephedrine component, Allegra-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR is 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 (e.g., 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 (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR concomitantly with other sympathomimetic amines because combined effects on the cardiovascular system may be harmful to the patient.

Drug Interactions with Antacids

• Administration of 120 mg of fexofenadine hydrochloride (2 x 60 mg capsule) within 15 minutes of an aluminum and magnesium containing antacid (Maalox) decreased fexofenadine AUC by 41% and Cmax by 43%.
• Allegra-D (fexofenadine hcl and pseudoephedrine hcl) 12 HOUR should not be taken closely in time with aluminum and magnesium containing antacids.

Interactions with Fruit Juices

• Fruit juices such as grapefruit, orange and apple may reduce the bioavailability and exposure of fexofenadine.
• This is based on the results from 3 clinical studies using histamine induced skin wheals and flares coupled with population pharmacokinetic analysis.
• The size of wheal and flare were significantly larger when fexofenadine hydrochloride was administered with either grapefruit or orange juices compared to water.
• Based on the literature reports, the same effects may be extrapolated to other fruit juices such as apple juice.
• The clinical significance of these observations is unknown.
• In addition, based on the population pharmacokinetics analysis of the combined data from grapefruit and orange juices studies with the data from a bioequivalence study, the bioavailability of fexofenadine was reduced by 36%.
• Therefore, to maximize the effects of fexofenadine, it is recommended that Allegra-D 12 HOUR should be taken with water.