Fexofenadine

Last updated

Fexofenadine
Fexofenadine2DCSD.svg
Fexofenadine 3D ball.png
Clinical data
Trade names Allegra, others
AHFS/Drugs.com Monograph
MedlinePlus a697035
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Antihistamine; H1 receptor antagonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 30–41% [8]
Protein binding 60–70% [9]
Metabolism Hepatic (≤5% of dose) [9]
Elimination half-life 14.4 hours
Excretion Feces (~80%) and urine (~10%) as unchanged drug [9]
Identifiers
  • (±)-4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α, α-dimethyl benzeneacetic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.228.648 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C32H39NO4
Molar mass 501.667 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • O=C(O)C(c1ccc(cc1)C(O)CCCN2CCC(CC2)C(O)(c3ccccc3)c4ccccc4)(C)C
  • InChI=1S/C32H39NO4/c1-31(2,30(35)36)25-17-15-24(16-18-25) 29(34)14-9-21-33-22-19-28(20-23-33)32(37, 26-10-5-3-6-11-26)27-12-7-4-8-13-27/h3-8, 10-13,15-18,28-29,34,37H,9,14,19-23H2,1-2H3,(H,35,36) X mark.svgN
  • Key:RWTNPBWLLIMQHL-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Fexofenadine, sold under the brand name Allegra among others, [10] is an antihistamine pharmaceutical drug used in the treatment of allergy symptoms, such as hay fever and urticaria. [11]

Contents

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. [12] [13]

It was patented in 1979 and came into medical use in 1996. [14] It is on the World Health Organization's List of Essential Medicines. [15] Fexofenadine has been manufactured in generic form since 2011. [16] In 2022, it was the 257th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [17] [18]

Medical uses

Fexofenadine is used for relief from physical symptoms associated with seasonal allergic rhinitis and for treatment of hives, including chronic urticaria. [12] 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 drug to use for individuals with inherited long QT syndrome. [19]

Efficacy

For the treatment of allergic rhinitis, fexofenadine is similarly effective to cetirizine, but is associated with less drowsiness than cetirizine. [20] Fexofenadine was also shown to inhibit histamine-induced wheal and flare to a significantly greater degree than loratadine or desloratadine, [21] but was slightly less effective than levocetirizine. [22]

Fexofenadine at doses above 120 mg a day does not appear to provide additional efficacy in the treatment of allergic rhinitis. [23] [24]

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. [5]

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. [25] 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. [5] If an 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. [5]

Pharmacology

Pharmacodynamics

Fexofenadine is a selective peripheral H1 receptor 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. [5] [26]

Fexofenadine also exhibits no anticholinergic, antidopaminergic, antiserotonergic, alpha 1-adrenergic, or beta-adrenergic receptor-blocking effects. [5]

Pharmacokinetics

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). [5] 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.[ 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. [5] Grapefruit juice can significantly reduce the plasma concentration of fexofenadine. [27]

Antacids containing aluminum or magnesium should not be taken within 15 minutes of fexofenadine, as they reduce its absorption by almost 50%. [5] 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. [28]

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. [29] 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 which enabled the growth of AMRI.[ citation needed ]

In January 2011, the FDA approved over-the-counter sales of fexofenadine in the United States, and Sanofi Aventis' version became available in March 2011. [30] In December 2020, the MHRA reclassified fexofenadine from prescription only to allow general sales in the United Kingdom. [31]

Society and culture

Brand names

Fexofenadine is marketed under many brand names worldwide. [10]

As of January 2017, it is marketed as a combination drug with pseudoephedrine under brand names including Alerfedine D, Allegra-D, Allergyna-D, Allevia, Altiva-D, Dellegra, Fexo Plus, Fexofed, Fixal Plus, Ridrinal D, Rinolast D, Telfast D, and Treathay. [10]

As of January 2017, it is marketed as a combination drug with montelukast under brand names including Fexokast, Histakind-M, Monten-FX, Montolife-FX, Montair-FX and Novamont-FX. [10]

Related Research Articles

H1 antagonists, also called H1 blockers, are a class of medications that block the action of histamine at the H1 receptor, helping to relieve allergic reactions. Agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed antihistamines; other agents may have antihistaminergic action but are not true antihistamines.

<span class="mw-page-title-main">Allergic rhinitis</span> Nasal inflammation due to allergens in the air

Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. It is classified as a type I hypersensitivity reaction. Signs and symptoms include a runny or stuffy nose, sneezing, red, itchy, and watery eyes, and swelling around the eyes. The fluid from the nose is usually clear. Symptom onset is often within minutes following allergen exposure, and can affect sleep and the ability to work or study. Some people may develop symptoms only during specific times of the year, often as a result of pollen exposure. Many people with allergic rhinitis also have asthma, allergic conjunctivitis, or atopic dermatitis.

<span class="mw-page-title-main">Loratadine</span> Antihistamine medication

Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies. This includes allergic rhinitis and hives. It is also available in drug combinations such as loratadine/pseudoephedrine, in which it is combined with pseudoephedrine, a nasal decongestant. It is taken orally.

<span class="mw-page-title-main">Hydroxyzine</span> Antihistamine drug

Hydroxyzine, sold under the brand names Atarax and Vistaril among others, is an antihistamine medication. It is used in the treatment of itchiness, anxiety, insomnia, and nausea. It is used either by mouth or injection into a muscle.

<span class="mw-page-title-main">Desloratadine</span> Allergy medication

Desloratadine sold under the brand name Clarinex among others, is a tricyclic H1 inverse agonist that is used to treat allergies. It is an active metabolite of loratadine.

<span class="mw-page-title-main">Cetirizine</span> Antihistamine medication

Cetirizine is a second-generation antihistamine used to treat allergic rhinitis, dermatitis, and urticaria (hives). It is taken by mouth. Effects generally begin within thirty minutes and last for about a day. The degree of benefit is similar to other antihistamines such as diphenhydramine, which is a first-generation antihistamine.

<span class="mw-page-title-main">Olopatadine</span> Chemical compound

Olopatadine, sold under the brand name Patanol among others, is an antihistamine medication used to decrease the symptoms of allergic conjunctivitis and allergic rhinitis. It is used as eye drops or as a nasal spray. The eye drops generally result in an improvement within half an hour.

<span class="mw-page-title-main">Levocetirizine</span> Antihistamine drug

Levocetirizine, sold under the brand name Xyzal, among others, is a second-generation antihistamine used for the treatment of allergic rhinitis and long-term hives of unclear cause. It is less sedating than older antihistamines. It is taken by mouth.

<span class="mw-page-title-main">Terfenadine</span> Chemical compound

Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel and was marketed under various brand names, including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia. It was superseded by fexofenadine in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart and has been withdrawn from markets worldwide.

<span class="mw-page-title-main">Azelastine</span> Chemical compound

Azelastine, sold under the brand name Astelin among others, is a H1 receptor-blocking medication primarily used as a nasal spray to treat allergic rhinitis (hay fever) and as eye drops for allergic conjunctivitis. Other uses may include asthma and skin rashes for which it is taken by mouth. Onset of effects is within minutes when used in the eyes and within an hour when used in the nose. Effects last for up to 12 hours.

<span class="mw-page-title-main">Acrivastine</span> Chemical compound

Acrivastine is a medication used for the treatment of allergies and hay fever. It is a second-generation H1-receptor antagonist antihistamine and works by blocking histamine H1 receptors.

<span class="mw-page-title-main">Mequitazine</span> Chemical compound

Mequitazine (trade name Primalan) is an H1 antagonist and anticholinergic of the phenothiazine chemical class. It is used to treat allergies and rhinitis.

<span class="mw-page-title-main">Ebastine</span> Antihistamine drug

Ebastine is a H1 antihistamine with low potential for causing drowsiness.

<span class="mw-page-title-main">Rupatadine</span> Second generation H1-antihistamine

Rupatadine is a second generation antihistamine and platelet-activating factor antagonist used to treat allergies. It was discovered and developed by Uriach and is marketed as Rupafin and under several other trade names.

<span class="mw-page-title-main">Antihistamine</span> Drug that blocks histamine or histamine agonists

Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic drug that can be bought without a prescription and provides relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection. Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.

<span class="mw-page-title-main">Bilastine</span> Antihistamine medication

Bilastine is an antihistamine medication used to treat hives (urticaria), allergic rhinitis and itchy inflamed eyes (allergic conjunctivitis) caused by an allergy. It is a second-generation antihistamine and takes effect by selectively inhibiting the histamine H1 receptor, preventing these allergic reactions. Bilastine has an effectiveness similar to cetirizine, fexofenadine, and desloratadine.

<span class="mw-page-title-main">Ze339</span> Brand of herbal extracts

Ze339 brand herbal extracts are taken from the leaves of a unique variety (Petzell) of the butterbur plant. Petzell is grown on GAP-managed farms in Europe.

Fexofenadine/pseudoephedrine, sold under the brand name Allegra-D among others, is a fixed-dose combination medication used for the treatment of nasal congestion and other symptoms of allergies and the common cold. It contains fexofenadine, as the hydrochloride, an antihistamine; and pseudoephedrine, as the hydrochloride, a nasal decongestant.

Cetirizine/pseudoephedrine (Zyrtec-D) is an antihistamine and decongestant formulation. It is a fixed-dose combination drug containing 5 mg cetirizine hydrochloride and 120 mg pseudoephedrine hydrochloride for symptoms related to seasonal allergic rhinitis. Cetirizine/pseudoephedrine gained approval from the U.S. Food and Drug Administration in 2001 as a prescription drug and became over-the-counter (OTC) in 2007.

Anti-allergic agents are medications used to treat allergic reactions. Anti-allergic agents have existed since 3000 B.C in countries such as China and Egypt. It was not until 1933 when antihistamines, the first type of anti-allergic agents, were developed. Common allergic diseases include allergic rhinitis, allergic asthma and atopic dermatitis with varying symptoms, including runny nose, watery eyes, itchiness, coughing, and shortness of breath. More than one-third of the world's population is currently being affected by one or more allergic conditions.

References

  1. ↑ "Fexofenadine Use During Pregnancy". Drugs.com. 1 April 2019. Retrieved 26 July 2020.
  2. ↑ "Telfast 30mg Film-coated Tablets - Summary of Product Characteristics (SmPC)". (emc). 25 October 2019. Retrieved 20 June 2021.
  3. ↑ "Almerg 180 mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 20 June 2021.
  4. ↑ "Fexofenadine Hydrochloride 120 mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". (emc). 22 March 2021. Archived from the original on 24 June 2021. Retrieved 20 June 2021.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Allegra (fexofenadine hydrochloride) tablet, orally disintegrating for oral use Allegra (fexofenadine hydrochloride) tablet, film coated for oral use Allegra (fexofenadine hydrochloride) suspension for oral useInitial U.S. Approval: 1996". DailyMed. 15 December 2008. Retrieved 13 February 2022.
  6. ↑ "Allegra Allergy- fexofenadine hydrochloride tablet, coated". DailyMed. Retrieved 12 February 2022.
  7. ↑ "ALLEGRA (fexofenadine hydrochloride) Product Monograph" (PDF). Sanofi Consumer Health Inc. 7 November 2019.
  8. ↑ Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Houston B, et al. (May 2010). "Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability". European Journal of Pharmaceutical Sciences. 40 (2): 125–131. doi:10.1016/j.ejps.2010.03.009. PMID   20307657.
  9. 1 2 3 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): 813–822. doi:10.1517/17425250903044967. PMID   19545214. S2CID   19048690.
  10. 1 2 3 4 "Fexofenadine - international brand names". Drugs.com. Retrieved 18 January 2017.
  11. ↑ 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". Clinical Therapeutics. 31 (5): 921–944. doi:10.1016/j.clinthera.2009.05.017. PMID   19539095.
  12. 1 2 Compalati E, Baena-Cagnani R, Penagos M, Badellino H, Braido F, Gómez RM, et al. (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.
  13. ↑ Dicpinigaitis PV, Gayle YE (November 2003). "Effect of the second-generation antihistamine, fexofenadine, on cough reflex sensitivity and pulmonary function". British Journal of Clinical Pharmacology. 56 (5): 501–504. doi:10.1046/j.1365-2125.2003.01902.x. PMC   1884387 . PMID   14651723.
  14. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 548. ISBN   9783527607495.
  15. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  16. ↑ "Dr. Reddy's announces the launch of Over-the-Counter Fexofenadine HCl and Pseudoephedrine HCl extended-release tablets". Dr. Reddy's Laboratories Ltd. 30 August 2011. Archived from the original on 12 October 2016. Retrieved 27 May 2016.
  17. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  18. ↑ "Fexofenadine Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  19. ↑ Welzel T, Ziesenitz VC, Seitz S, Donner B, van den Anker JN (November 2018). "Management of anaphylaxis and allergies in patients with long QT syndrome: A review of the current evidence". Annals of Allergy, Asthma & Immunology. 121 (5): 545–551. doi: 10.1016/j.anai.2018.07.027 . PMID   30059791.
  20. ↑ Hampel F, Ratner P, Mansfield L, Meeves S, Liao Y, Georges G (October 2003). "Fexofenadine hydrochloride, 180 mg, exhibits equivalent efficacy to cetirizine, 10 mg, with less drowsiness in patients with moderate-to-severe seasonal allergic rhinitis". Annals of Allergy, Asthma & Immunology. 91 (4): 354–361. doi:10.1016/S1081-1206(10)61682-1. PMID   14582814.
  21. ↑ Kruszewski J, Kłos K, Sułek K (November 2006). "[Inhibition of histamine-induced wheel after a recommended single dose administration of 10 mg cetirizine, 5 mg desloratadine, 120 i 180 mg fexofenadine, 5 mg levocetirizine and 10 mg loratadine--a randomized, double-blind, placebo controlled trial]". Polski Merkuriusz Lekarski. 21 (125): 443–448. PMID   17345837.
  22. ↑ Grant JA, Riethuisen JM, Moulaert B, DeVos C (February 2002). "A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects". Annals of Allergy, Asthma & Immunology. 88 (2): 190–197. doi:10.1016/S1081-1206(10)61995-3. PMID   11868924.
  23. ↑ Casale TB, Andrade C, Qu R (1999). "Safety and efficacy of once-daily fexofenadine HCl in the treatment of autumn seasonal allergic rhinitis". Allergy and Asthma Proceedings. 20 (3): 193–198. doi:10.2500/108854199778553046. PMID   10389553.
  24. ↑ Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J (November 1999). "Double-blind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis". The Journal of Allergy and Clinical Immunology. 104 (5): 927–933. doi: 10.1016/s0091-6749(99)70070-9 . PMID   10550734.
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  27. ↑ Shirasaka Y, Mori T, Murata Y, Nakanishi T, Tamai I (August 2014). "Substrate- and dose-dependent drug interactions with grapefruit juice caused by multiple binding sites on OATP2B1". Pharmaceutical Research. 31 (8): 2035–2043. doi:10.1007/s11095-014-1305-7. PMID   24549825. S2CID   17532347.
  28. ↑ Shehnaz H, Haider A, Arayne MS, Sultana N (November 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 .
  29. ↑ Daniel Lednicer (1999). The Organic Chemistry of Drug Synthesis. Vol. 6. New York: Wiley Interscience. pp. 38–40. ISBN   978-0-471-24510-0.
  30. ↑ "Allegra FAQs". Sanofi-Aventis. Archived from the original on 20 May 2011. Retrieved 5 July 2011.
  31. ↑ "PAR: Reclassification of Allevia 120mg tablets from Prescription Only Medicine (POM) to General Sales List (GSL)". MHRA. 22 December 2020.
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