Fexofenadine

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Fexofenadine
Skeletal formula of fexofenadine
Ball-and-stick model of fexofenadine
Clinical data
Trade namesAllegra, FX 24, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa697035
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S2 (Pharmacy medicine) / S4
  • BR: OTC (Over the counter)
  • CA: OTC
  • UK: POM (Prescription only) / P/ GSL[3][4][5]
  • US: OTC / Rx-only
Pharmacokinetic data
Bioavailability30–41%[6]
Protein binding60–70%[7]
MetabolismHepatic (≤5% of dose)[7]
Elimination half-life14.4 hours
ExcretionFeces (~80%) and urine (~10%) as unchanged drug[7]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.228.648 Edit this at Wikidata
Chemical and physical data
FormulaC32H39NO4
Molar mass501.667 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
 ☒NcheckY (what is this?)  

Fexofenadine, sold under the brand name Allegra among others,[1] is an antihistamine pharmaceutical drug used in the treatment of allergy symptoms, such as hay fever and urticaria.[8]

Therapeutically, fexofenadine is a selective peripheral H1 blocker. It is classified as a second-generation antihistamine because it is less able to pass the blood–brain barrier and cause sedation, compared to first-generation antihistamines.[9][10] It has also been called a third-generation antihistamine, although some controversy is associated with the use of the term.[11]

It was patented in 1979 and came into medical use in 1996.[12] Fexofenadine has been manufactured in generic form since 2011.[13] In 2017, it was the 245th-most commonly prescribed medication in the United States, with more than one million prescriptions.[14][15]

Medical uses[]

Fexofenadine is used for relief from physical symptoms associated with seasonal allergic rhinitis and for treatment of chronic urticaria.[9] It does not cure, but rather prevents the aggravation of allergic rhinitis and chronic idiopathic urticaria, and reduces the severity of the symptoms associated with those conditions, providing relief from repeated sneezing, runny nose, itchy eyes or skin, and general body fatigue. In a 2018 review, fexofenadine, along with levocetirizine, desloratadine, and cetirizine, was cited to be a safe to use for individuals with inherited long QT syndrome.[16]

Side effects[]

The most common side effects include headache, back and muscle pain, miosis or pinpoint pupils, nausea, drowsiness, and menstrual cramps. Anxiety and insomnia have also been rarely reported. The most common side effects demonstrated during clinical trials were cough, upper respiratory tract infection, fever, and otitis media for children ages 6 to 11 and fatigue for children ages 6 months to 5 years.[17] A patient over the age of 80 experienced auditory hallucinations and extreme energy bursts.[medical citation needed]

Overdose[]

The safety profile of fexofenadine is quite favorable, as no cardiovascular or sedative effects have been shown to occur even when taking 10 times the recommended dose.[18] Research on humans ranges from a single 800-mg dose, to a twice-daily, 690-mg dose for a month, with no clinically significant adverse effects, when compared to a placebo. No deaths occurred in testing on mice, at 5000 mg/kg body weight, which is 110 times the maximum recommended dose for an adult human.[17] If overdose were to occur, supportive measures are recommended. Theoretically, an overdose could present as dizziness, dry mouth, and/or drowsiness, consistent with an exaggeration of the usual side effects. Hemodialysis does not appear to be an effective means of removing fexofenadine from the blood.[17]

Mechanism of action[]

Fexofenadine is a selectively peripheral H1 antagonist. Blockage prevents the activation of the H1 receptors by histamine, preventing the symptoms associated with allergies from occurring. Fexofenadine does not readily cross the blood–brain barrier, so is less likely to cause drowsiness in comparison to other antihistamines that readily cross that barrier (i.e. first-generation antihistamines such as diphenhydramine). In general, fexofenadine takes about an hour to take effect, though this may be affected by the choice of dosage form and the presence of certain foods.[19][20]

Fexofenadine also exhibits no anticholinergic, antidopaminergic, alpha 1-adrenergic, or beta-adrenergic receptor-blocking effects.[17]

Pharmacokinetics[]

  • Absorption: After oral application, maximum plasma concentrations are reached after 2–3 hours. Fexofenadine should not be taken with a high-fat meal, as mean concentrations of fexofenadine in the bloodstream are seen to be reduced from 20–60% depending on form of medication (tablet, ODT, or suspension).[17]
  • Distribution: Fexofenadine is 60–70% bound to plasma proteins, mostly albumin.[17]
  • Metabolism: Fexofenadine is a substrate of CYP3A4, but only about 5% is metabolized by the liver, indicating that hepatic metabolism is relatively minor in clearance from the body.[17]
  • Elimination: Most of the substance is eliminated unchanged via the feces (80%) and urine (11–12%).[17]

Interactions[]

Taking erythromycin or ketoconazole while taking fexofenadine does increase the plasma levels of fexofenadine, but this increase does not influence the QT interval. The reason for this effect is likely due to transport-related effects, specifically involving p-glycoprotein (p-gp).[17] Both erythromycin and ketoconazole are inhibitors of p-gp, a transporter protein involved in preventing the intestinal absorption of fexofenadine. When p-gp is inhibited, fexofenadine may be better absorbed by the body, increasing its plasma concentration by more than intended.[medical citation needed]

Fexofenadine is not to be taken with apple, orange, or grapefruit juice because they could decrease absorption of the drug. Therefore, it should be taken with water.[17] Grapefruit juice can significantly reduce the plasma concentration of fexofenadine.[21]

Antacids containing aluminum or magnesium should not be taken within 15 minutes of fexofenadine, as they reduce its absorption by almost 50%.[17] This is not thought to be due to a change in pH (in fact, absorption can actually increase under increasingly alkaline pH), but rather due to the formation of metal complexes with charged/polar moieties on fexofenadine. As suggested by Shehnaza et al (2014), various sites of the molecule are thought to be responsible for this interaction, including the piperidine nitrogen, the carboxylic acid (-COOH) group, and both hydroxyl (-OH) groups.[22]

Special populations[]

In the United States, fexofenadine is classified as pregnancy category C, and should only be used if the benefits outweigh the risks.[23][2] No studies have been done to evaluate the presence of fexofenadine in breast milk. Therefore, nursing women are urged to take caution while using fexofenadine.[17] No sufficient studies have been done in patients over age 65, so elderly patients are advised to use caution when using fexofenadine, particularly when concern for renal impairment exists.[17]

History[]

The older antihistaminic agent terfenadine was found to metabolize into the related carboxylic acid, fexofenadine. Fexofenadine was found to retain all of the biological activity of its parent, while giving fewer adverse reactions in patients, so terfenadine was replaced in the market by its metabolite.[24] Fexofenadine was originally synthesized in 1993 by Massachusetts-based biotechnology company Sepracor, which then sold the development rights to Hoechst Marion Roussel (now part of Sanofi-Aventis), and was later approved by the U.S. Food and Drug Administration (FDA) in 1996. Albany Molecular Research Inc. (AMRI) holds the patents to the intermediates and production of fexofenadine HCl, along with Roussel. Since that time, it has achieved blockbuster drug status with global sales of US$1.87B in 2004 (with $1.49B coming from the United States). AMRI received royalty payments from Aventis that enabled the growth of AMRI.[citation needed]

On January 25, 2011, the FDA approved over-the-counter sales of fexofenadine in the United States, and Sanofi Aventis' version became available on March 4, 2011.[25]

Other brand names[]

Fexofenadine is marketed under many brand names worldwide as of January 2017, including: Agimfast, Alafree, Alanil, Alercas, Alerfedine, Alerix, Alertam, Alexia, Allegix, Allegra, Allegratab, Allemax, Allerfast, Allerfen, Allerfexo, Allergo, Allergyna, Allerphast, Alrin, Alterfast, Aller-Fex, Altifex, Altiva, Aspen, Axodin, Axofen, BiXin, Bosnum, Dinafex, Elwigra, Ewofex, Fastel, Fastofen, Fastway, Fe Min, Feksine, Fenadex, Fenadin, Fenafex, Fenax, Fenofex, Fentradol, Fesler, Fexadyne, Fexal, Fexalar, Fexallegra, Fexaway, Fexet, Fexgen, Fexidine, Fexigra, Fexine, Fexo, Fexodane, Fexodine, Fexodis, Fexofast, Fexofen, Fexofenaderm, Fexofenadin, Fexofenadina, Fexofenadine, Fexofénadine, Fexofep, Fexofin, Fexogen, Fexomin, Fexon, Fexona, Fexonadinea, Fexoquit, Fexoral, Fexoril, Fexostad, Fexotine, Fexovid, Fixal, Fixit, Fixodin, Flexofen, Foxin, Fynadin, Glodas, Hasalfast, Histafree, Imexofen, Kofixir, Lai Duo Fei, Mayfex, Min Jie, Nefoxef, Neofex, Nolargy, Nosedex, Odafen, Oregra, Radifex, Raltiva, Rapido, Rhinogan, Ridrinal, Rinofen, Rinolast, Ritch, Rui Fei, Sailexi, Tefodine, Telfadin, Telfast, Telfastin, Telfexo, Tellerge, Terfemax, Ternafast, Tocimat, Tofexo, Torfast, Vifas, Vifasesh, X-Dine, Xergic, and Zefeksal.[1]

As of January 2017, it was marketed as a combination drug with pseudoephedrine under brand names including: Alerfedine D, Allegra-D, Allergyna-D, Altiva-D, Dellegra, Fexo Plus, Fexofed, Fixal Plus, Ridrinal D, Rinolast D, and Telfast D.[1]

As of January 2017, it was marketed as a combination drug with montelukast under brand names including Fexokast, Histakind-M, Monten-FX, Montolife-FX, Montair-FX and Novamont-FX.[1]

References[]

  1. ^ Jump up to: a b c d e "Fexofenadine - international brand names". Drugs.com. Retrieved 18 January 2017.
  2. ^ Jump up to: a b "Fexofenadine Use During Pregnancy". Drugs.com. 1 April 2019. Retrieved 26 July 2020.
  3. ^ "Telfast 30mg Film-coated Tablets - Summary of Product Characteristics (SmPC)". (emc). 25 October 2019. Retrieved 20 June 2021.
  4. ^ "Almerg 180 mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 20 June 2021.
  5. ^ "Fexofenadine Hydrochloride 120 mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". (emc). 22 March 2021. Retrieved 20 June 2021.
  6. ^ Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Houston B, Oosterhuis B, Bjerrum OJ, Rowland M, Garner C (May 2010). "Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability". Eur J Pharm Sci. 40 (2): 125–31. doi:10.1016/j.ejps.2010.03.009. PMID 20307657.
  7. ^ Jump up to: a b c Smith, SM; Gums, JG (July 2009). "Fexofenadine: biochemical, pharmacokinetic and pharmacodynamic properties and its unique role in allergic disorders". Expert Opinion on Drug Metabolism & Toxicology. 5 (7): 813–22. doi:10.1517/17425250903044967. PMID 19545214. S2CID 19048690.
  8. ^ Bachert, C (May 2009). "A review of the efficacy of desloratadine, fexofenadine, and levocetirizine in the treatment of nasal congestion in patients with allergic rhinitis". Clin Ther. 31 (5): 921–44. doi:10.1016/j.clinthera.2009.05.017. PMID 19539095.
  9. ^ Jump up to: a b Compalati, E; Baena-Cagnani, R; Penagos, M; Badellino, H; Braido, F; Gómez, RM; Canonica, GW; Baena-Cagnani, CE (2011). "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. 156 (1): 1–15. doi:10.1159/000321896. PMID 21969990.
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  14. ^ "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
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  19. ^ http://products.sanofi.ca/en/allegra.pdf
  20. ^ Stoltz, Maxine; Arumugham, Thangam; Lippert, Christina; Yu, Dale; Bhargava, Vijay; Eller, Mark; Weir, Scott (1997). "Effect of food on the bioavailability of fexofenadine hydrochloride (MDL 16 455A)". Biopharmaceutics & Drug Disposition. 18 (7): 645–648. doi:10.1002/(SICI)1099-081X(199710)18:7<645::AID-BDD50>3.0.CO;2-3.
  21. ^ Shirasaka, Y; Mori T; Murata Y; Nakanishi T; Tamai I (Feb 19, 2014). "Substrate- and Dose-Dependent Drug Interactions with Grapefruit Juice Caused by Multiple Binding Sites on OATP2B1". Pharm Res. 31 (8): 2035–2043. doi:10.1007/s11095-014-1305-7. PMID 24549825. S2CID 17532347.
  22. ^ Shehnaza, Hina; Haider, Amir; Arayne, M. Saeed; Sultana, Najma (Nov 2014). "Carboxyterfenadine antacid interaction monitoring by UV spectrophotometry and RP-HPLC techniques". Arabian Journal of Chemistry. 7 (5): 839–845. doi:10.1016/j.arabjc.2013.01.011.
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