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Fexofenadine


Fexofenadine

Article Author:
Kari Craun
Article Editor:
Mark Schury
Updated:
11/20/2020 7:33:10 PM
For CME on this topic:
Fexofenadine CME
PubMed Link:
Fexofenadine

Indications

Fexofenadine is a metabolite of terfenadine and is a second-generation antihistamine. It is FDA approved to treat both seasonal allergic rhinitis and chronic idiopathic urticaria.

  • Seasonal allergic rhinitis is characterized by symptoms including nasal itching, sneezing, rhinorrhea, and nasal congestion, though antihistamines are less useful for nasal congestion symptoms. The trigger for these symptoms can be a number of allergens, which are seasonal or perennial and include grass, pollens, dust, pet dander, mold, and others.[1]
    • Compared with loratadine in a double-blind, placebo-controlled, randomized trial, fexofenadine and loratadine had similar safety and efficacy. However, fexofenadine worked more effectively for eye symptoms and nasal congestion symptoms.[2]
  • As the name implies, chronic idiopathic urticaria is a chronic condition that is due to spontaneous mast cell degranulation [1]. Symptomatic triggers include water, sweat, sun, cold, or pressure and can include dermatographism and urticarial rash.

Fexofenadine has approval for use in both children and adults. Children should be six months old or older, dependent upon the indication for use.[3] Specific dosing is discussed below in the administration section.

Mechanism of Action

The mechanism of action of fexofenadine is to selectively antagonize H1 receptors on the surface of cells on multiple different organ systems. It is a second-generation H1 receptor blocker and is non-sedating. Fexofenadine also affects inflammatory mediators.[4][5] Fexofenadine does not cross the blood-brain barrier and thus does not cause drowsiness like other H1 blockers. Second-generation antihistamines such as fexofenadine have less affinity for cholinergic and alpha-adrenergic receptors and therefore do not display the anticholinergic side effects that other antihistamines do. Fexofenadine can also inhibit other mechanisms such as mast cell, basophilic histamine, and inflammatory cell release.

The onset of action is about 2 hours and is long-acting, which allows for once a day administration.[6] While the metabolism of other antihistamines occurs in the liver, fexofenadine is hepatically cleared to a lesser degree than others and excreted in the stool.[1]

Administration

Fexofenadine comes in multiple different forms. It may be administered orally as a tablet, oral suspension (syrup), or branded oral disintegrating tablets. Fexofenadine may be used in adults and children, though the dose for children is lower than that of an adult (up to 60 mg vs. 180 mg daily PO).[7]

  • In adults:
    • Dosing for seasonal allergic rhinitis and chronic urticaria is the same: 60 mg PO BID or 180 mg PO daily.
  •  In pediatrics, dosing differs based on age and indication.
    • For seasonal allergic rhinitis: 
      • Not approved for use in children less than 2 years of age
      • Children 2-12 years old: 30 mg PO BID
      • Children older than 12 years old: 60 mg PO BID or 180 mg PO daily
    • For chronic urticaria:
      • Not approved for use in infants less than 6 months old
      • Children 6 months to 2 years old: 15 mg PO BID
      • Children 2 to 12 years old: 30 mg PO BID
      • Children older than 12 years: 60 mg PO BID or 180 mg PO daily
  • Renal impairment with creatinine clearance less than 80 ml/min:
    • Adults should take 60 mg PO daily.
    • Dosing for pediatric patients with renal impairment vary by age as follows:
      • Children 6 months to 2 years old: 15 mg PO daily
      • Children 2 to 12 years old: 30 mg PO daily
      • Children older than 12 years: 60 mg PO daily

ODT tablets are branded and should be placed on the tongue, allowed to dissolve (with or without water) then swallowed. Patients should not chew them, and patients should take the medication before eating or drinking anything.

  • ODT tablets are typically used in pediatric patients, and dosing is 30 mg PO BID for ages 6 to 12 for both seasonal allergic rhinitis and chronic urticaria.

No matter the administration route, it is important to note that taking the drug with grapefruit, apple, or orange juice decreases bioavailability. This reduced bioavailability is because of the inhibition of P-glycoprotein transporter (P-gp). Patients should separate the administration of fexofenadine and any of these juices by at least 4 hours.

Adverse Effects

Reported side effects in a meta-analysis of other random, double-blind, placebo-controlled study versus placebo are as follows:

  • Headache
  • Nose bleeds
  • Upper respiratory complaints including infection, sore throat, cough, and sinusitis
  • Rash
  • Asthma
  • Infection
  • GI symptoms including abdominal pain, nausea, and diarrhea
  • Leukopenia
  • Back pain
  • Weakness
  • Sedation/drowsiness
  • Dry mouth[8]

The most frequently occurring side effects of these are drowsiness, fatigue, and dry mouth, which may occur at larger doses.

Contraindications

Hypersensitivity to fexofenadine or any of its components is the only true contraindication to this medication's use. There is little hepatic involvement in the clearance of this medication, so it is safe for use in patients with liver pathology. Caution is necessary when treating patients with renal disease, and renal dosing, as noted above, should be followed.

There is no significant interaction with fexofenadine and concomitant use of alcohol or food. However, bioavailability decreases when used with grapefruit, apple, or orange juices.[9]

 In animal models, fexofenadine has been shown to cause low birth weight and is currently a category C medication in pregnancy. Alternatives for symptom relief of allergic rhinitis include loratadine and cetirizine.[10]

Monitoring

Monitoring fexofenadine involves monitoring for improvement or worsening of symptoms with use. Because of fexofenadine's close relationship with cardiotoxic terfenadine, patients with underlying cardiac conditions may need to be monitored with periodic EKG to watch for QT-prolongation and arrhythmias.

A study out of Vietnam compared fexofenadine and levocetirizine for chronic urticaria. The study found that at doses that were two times the recommended dosing showed improved urticarial symptoms without increasing negative side effects. The most common side effects noted were fatigue and drowsiness, which occurred at the same rates in patients taking the recommended dose rather than the higher dose. This same study mentions a European study in which dosing was quadrupled and still had similar side effects.[11]

Toxicity

As previously mentioned, fexofenadine is a metabolite of terfenadine, which proved to have cardiotoxic effects. Terfenadine blocked cardiac potassium channels, which, when taken in large doses or with other medications such as ketoconazole, caused prolonged QT-interval. Prolonged QT-interval can lead to fatal arrhythmias. Fexofenadine has replaced terfenadine in the United States per FDA guidelines because it does not block potassium channels. In multiple studies, it did not cause any arrhythmias or significant prolonged QT-intervals.

Despite the findings of these studies, other case reports have found a relationship between fexofenadine and QT-interval elongation and ventricular arrhythmia though it is very rare. It bears mentioning that the use of fexofenadine with hepatic CYP3A4 blockers (such as erythromycin, ketoconazole) can increase its concentration in the blood, and combined use with drugs such as rifampin and troglitazone will decrease the concentration. These effects are likely due to the interaction between these compounds and the P-glycoprotein transporter, removing fexofenadine from the blood.[12]

Enhancing Healthcare Team Outcomes

Fexofenadine is a commonly used medication for seasonal allergic rhinitis and chronic urticaria and is an overall safe and effective therapy when used properly. While it is available to patients without a prescription, care is necessary when starting any new medication. Patients should discuss the use of fexofenadine with their primary care physician and pharmacist to educate themselves on side effects, recommended dosing, and possible interactions with commonly ingested items such as fruit juices. Providers should ensure that renal and pediatric patients are taking the appropriate adjusted dosage of fexofenadine. [Level 5]


References

[1] Randall KL,Hawkins CA, Antihistamines and allergy. Australian prescriber. 2018 Apr;     [PubMed PMID: 29670310]
[2] Van Cauwenberge P,Juniper EF, Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2000 Jun;     [PubMed PMID: 10848909]
[3] Devillier P,Roche N,Faisy C, Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine and levocetirizine : a comparative review. Clinical pharmacokinetics. 2008;     [PubMed PMID: 18336052]
[4] Mahatme MS,Dakhale GN,Tadke K,Hiware SK,Dudhgaonkar SD,Wankhede S, Comparison of efficacy, safety, and cost-effectiveness of montelukast-levocetirizine and montelukast-fexofenadine in patients of allergic rhinitis: A randomized, double-blind clinical trial. Indian journal of pharmacology. 2016 Nov-Dec;     [PubMed PMID: 28066101]
[5] Kawauchi H,Yanai K,Wang DY,Itahashi K,Okubo K, Antihistamines for Allergic Rhinitis Treatment from the Viewpoint of Nonsedative Properties. International journal of molecular sciences. 2019 Jan 8;     [PubMed PMID: 30626077]
[6] Simpson K,Jarvis B, Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs. 2000 Feb;     [PubMed PMID: 10730552]
[7] Meltzer EO,Scheinmann P,Rosado Pinto JE,Bachert C,Hedlin G,Wahn U,Finn AF Jr,Ruuth E, Safety and efficacy of oral fexofenadine in children with seasonal allergic rhinitis--a pooled analysis of three studies. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2004 Jun;     [PubMed PMID: 15209959]
[8] Compalati E,Baena-Cagnani R,Penagos M,Badellino H,Braido F,Gómez RM,Canonica GW,Baena-Cagnani CE, Systematic review on the efficacy of fexofenadine in seasonal allergic rhinitis: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials. International archives of allergy and immunology. 2011;     [PubMed PMID: 21969990]
[9] Paśko P,Rodacki T,Domagała-Rodacka R,Palimonka K,Marcinkowska M,Owczarek D, Second generation H1 - antihistamines interaction with food and alcohol-A systematic review. Biomedicine     [PubMed PMID: 28622592]
[10] Gonzalez-Estrada A,Geraci SA, Allergy Medications During Pregnancy. The American journal of the medical sciences. 2016 Sep;     [PubMed PMID: 27650241]
[11] Thi HT,Thi LP,Van TN,Minh PPT,Trong HN,Van TC,Huu SN,Minh TT,Huu ND,Van TH,Cam VT,Huyen ML,Hau KT,Thanh TN,Thi PH,Thuy LN,Gandolfi M,Satolli F,Feliciani C,Tirant M,Vojvodic A,Lotti T, The Efficacy of a Two-Fold Increase of H1-Antihistamine in the Treatment of Chronic Urticaria - the Vietnamese Experience. Open access Macedonian journal of medical sciences. 2019 Jan 30;     [PubMed PMID: 30745975]
[12] Paakkari I, Cardiotoxicity of new antihistamines and cisapride. Toxicology letters. 2002 Feb 28;     [PubMed PMID: 12052668]