Generic Name: Fexofenadine (multiple manufacturers)
Common Brand Name: Allegra (Sanofi-Aventis – U.S.)
Popularity: 33rd most commonly prescribed drug between 2002-2009 (U.S.)
Class: Antihistamine
Treatment Uses — For treatment of seasonal allergic rhinitis (sneezing, runny nose, itchy and watery eyes, etc.) and chronic idiopathic urticaria (hives and itching). Has been used with good results for perennial allergic rhinitis (perennial implies year-round versus seasonal — more commonly called “hay fever”) and as pretreatment for hymenoptera immunotherapy (venom immunotherapy for honey bee sting allergies) to decrease the extent of allergic reactions (localized and systemic).
Fexofenadine has been studied and shown ineffective at treating motion sickness. A single published case report described effective use of fexofenadine to treat solar (sun induced) urticaria. Fexofenadine appears to have no antitussive (cough inhibiting) properties.
Rhinitis affects up to 40 million people annually in the U.S., annoying some 10 to 30 percent of adults and up to 40 percent of children. First generation antihistamines such as chlorpheniramine, diphenhydramine, hydroxyzine, and promethazine were the mainstay of treatment until the mid-1980s. Unfortunately, these prototypical antihistamines have a significant CNS (Central Nervous System) side effect of sedation (some, in fact, are used for their sedative effects).
The first non-sedating antihistamine, terfenadine (Seldane) appeared on the market in 1985: a wonder drug for those with allergies. Terfenadine represented the first in a series of so called “second generation” antihistamines. As these drugs did not cross the blood-brain barrier, they lacked the dreaded sedating effects.
Between 1984 and 1996, the FDA (Food and Drug Administration) received 39 reports of torsade de pointes (TDP) associated with administration of terfenadine. It turned out that unmetabolized terfenadine induced a delayed cardiac repolarization that potentiated lethal heart rhythms (such as TDP). Patients taking antibiotics such as erythromycin, antifungal drugs like ketoconazole or those with liver disease alone all had delayed metabolism of terfenadine and were at risk of dangerous heart rhythms.
Fexofenadine, introduced in July 1996, did not have this cardiac side effect. The availability of this safer drug, coupled with pressure from the FDA, prompted Hoechst Marion Roussel to voluntarily withdraw terfenadine from the U.S. market on February 1, 1998. The drug is still sold in other countries, but is not actively marketed anywhere in the world.
Today, nonsedating antihistamines are preferred as first line therapy for allergies. Which nonsedating antihistamine is superior for allergic rhinitis has not been determined. In patients with chronic idiopathic urticaria, a greater number were symptom free with cetirizine than with fexofenadine in a 2004 study comparing the two drugs head to head. Cetirizine may, however, seems to be associated with more sedation than fexofenadine.
Dosing and Administration — The recommended dose of fexofenadine for allergic rhinitis and urticaria in adults and children aged 12 and older is 60 milligrams orally, twice daily (spaced 12 hours apart) or 180 milligrams once daily. For children from 2 to 11 years old, 30 milligrams twice daily is recommended and for children 6 months to 2 years of age, 15 milligrams twice daily. There are not adequate safety and dosing data for fexofenadine in children less than six months of age.
Fexofenadine comes in tablets, capsules, suspensions (liquid) and oral disintegrating tablets (ODT). At equal doses, all forms of fexofenadine appear equivalent.
When administered with food, onset of action is delayed and peak drug concentrations are significantly reduced. Fexofenadine should not be taken with food. Administration with grapefruit, orange or apple juice significantly impairs drug delivery; these drinks should be avoided with fexofenadine.
Some literature suggests that patients should never drink grapefruit, orange or apple juice. This is incorrect – they just should not drink these juices with or near the time they take fexofenadine. Use of aluminum or magnesium containing antacids within 15 minutes of taking fexofenadine also significantly impairs absorption.
In patients with kidney disease (decreased renal function), fexofenadine dosing should be decreased to half the recommended dosing for healthy patients (60 milligrams daily for adults, 30 milligrams daily for children from 2 to 11 years old and 15 milligrams daily for children 6 months to 2 years of age). No dosing adjustments appear necessary in older patients or in persons with liver (hepatic) dysfunction.
The most common symptoms associated with overdose have been dizziness, drowsiness and dry mouth. Studies of up to 5,000 milligrams per kilogram of fexofenadine in mice produced no fatalities. Single doses of up to 800 milligrams in human volunteers have produced no adverse side effects. In dogs, no evidence of toxicity was seen in doses up to 2,000 milligrams per kilogram. Hemodialysis is not effective in removing fexofenadine from the blood. Treatment of overdoses should be supportive.
Pharmacology/Pharmacokinetics/Stability — Following oral administration, fexofenadine is rapidly absorbed, exhibiting antihistaminic effects within one to two hours with peak effects seen between two and three hours. Duration of action ranges from 12 to 24 hours and is dose dependent. Of note, no tolerance to the effects of fexofenadine has been observed with long treatment durations (28 days). This is important as first generation antihistamines all exhibit tachyphylaxis, meaning that increasing doses are needed to achieve like effects when used for long periods of time. Second generation antihistamines do not appear to develop tachyphylaxis with long-term use.
Metabolism and kinetics of fexofenadine are not totally understood. It appears that only 5 percent of the drug is actually metabolized, some by the liver, some by the intestinal walls and some by intestinal bacteria. A small amount (0.5 to 1.5 percent) of each dose is converted by the cytochrome P450 isoenzyme system to inactive metabolite. Some 80 percent of fexofenadine is excreted in the feces and 11 percent excreted by the kidneys.
Available data on fexofenadine use during pregnancy show no increased risk of fetal harm however, studies are not sufficiently definitive. Studies in rats, rabbits and mice have not shown any direct harmful effects on fetuses. Until more human data are available, fexofenadine should be used during pregnancy only when benefits outweigh potential fetal risks. It is unknown whether fexofenadine is excreted in the breast milk of nursing mothers but the weight of evidence and expert consensus suggests that this drug poses minimal risk to the breastfed infant.
Fexofenadine is the active acid metabolite of terfenadine and works in the body as a selective H1-receptor antagonist (which means it inhibits histamine release from mast cells).
Fexofenadine comes in a variety of strength tablets, depending on manufacturer but typically 30, 60 and 180 milligram strengths. ODT tablets are typically available in 30 milligram strength and are intended to dissolve on the tongue and not be chewed. ODT foil blister packs should be protected from moisture and only removed from their package at the time of administration. Fexofenadine oral suspension is normally available in a 30 milligram in 5 milliliter concentration; shake well before using. Fexofenadine should be stored at room temperature (68 to 77 F).
Cautions and Warnings — While terfenadine was pulled from the market for inducing cardiac rhythm disturbances, equivalent doses of fexofenadine, and even doses up to 30 times equivalent terfenadine doses have not shown arrhythmogenic effects. Fexofenadine does prolong corrected QT (QTc) intervals yet these prolongations remain within normal QTc range limits. No adverse cardiovascular effects have been observed with fexofenadine even when combined with antibiotic or antifungals known to induce cardiac rhythm disturbances with terfenadine.
Important Side Effects and Interactions – The most common side effects reported with fexofenadine are headache (5 to 11 percent), vomiting in children (6 months to 5 year, 4 to 12 percent), somnolence or fatigue (1 to 3 percent), diarrhea (3 to 4 percent), musculoskeletal pain (2 to 3 percent) and dysmenorrhea (painful menstruation 2 percent). While sedation occurs in some patients taking fexofenadine, compared to other non-sedating (second generation) antihistamines (loratadine, cetirizine, and acrivastine), the incidence is lowest with fexofenadine.
Currently, there are 12 drugs reported to interact with fexofenadine. Of these, none are significant to prehospital and emergency medicine providers.
Average Costs – U.S.
• 60 mg tablet (generic fexofenadine)*
Patient cost: $0.48 each
Large Hospital cost: $0.41 each
*(Wal Mart® and Target don’t include this med in their $4/month programs)
References:
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed December, 2010).
2. Albany Medical Center Pharmacy, Albany, New York.
