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| Clinical data | |
|---|---|
| Trade names | Allegra |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a697035 |
| License data |
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| Pregnancy category |
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| Routes of administration | Oral |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 30-41% |
| Protein binding | 60-70% |
| Metabolism | Hepatic (5% of dose) |
| Elimination half-life | 14.4 hours |
| Excretion | Feces (~80%) and urine (~11%) as unchanged drug |
| Identifiers | |
IUPAC name
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| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.228.648  |
| Chemical and physical data | |
| Formula | C32H39NO4 |
| Molar mass | 501.656 g·mol |
| 3D model (JSmol) | |
SMILES
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InChI
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| (what is this?) (verify) | |
Fexofenadine (trade names Allegra, Telfast, Fastofen, Tilfur, Vifas, Telfexo, Allerfexo) is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. It was developed as a successor of and alternative to terfenadine (trade names include Triludan and Seldane), an antihistamine that caused QT interval prolongation, potentially leading to cardiac arrhythmia. Fexofenadine, like other second- and third-generation antihistamines, does not readily cross the blood-brain barrier, and so causes less drowsiness than first-generation histamine-receptor antagonists. It works by being an antagonist to the H1 receptor.
It has been described as both a second-generation and third-generation antihistamine.
Indications
Fexofenadine is indicated for the relief from physical symptoms associated with seasonal allergic rhinitis and treatment of chronic urticaria. It is not a therapeutic drug and does not cure but rather prevents the aggravation of rhinitis and urticaria and reduces the severity of the symptoms associated with those conditions, providing much relief from repeated sneezing, runny nose, itchy eyes and general body fatigue.
Dosage
- Children of 12 years and older, adults: 60 mg twice daily or 180 mg once daily
- Elderly: Starting dose: 60 mg once daily
Fexofenadine is not well examined for children under 12 years.
Dosage forms
- Suspension: 6 mg/mL (300 mL)
- Tablet: 30 mg, 60 mg, 180 mg
- Orally-disintegrating tablet: 30 mg
- Some preparations are combined with 120 mg (12 hour extended release dosage form) or 240 mg (24 hour extended release dosage form) of pseudoephedrine as a decongestant.
Side effects
The most common side effects are headache, nausea, dizziness, drowsiness and sleepiness; nervousness nightmares and frequent coughing are seen in less than 1% of patients. In studies, all of these effects occurred with similar frequencies as under placebo.
Overdose
Reports of fexofenadine overdose are infrequent, and because of this, the effects are not well established. No deaths occurred in testing on mice, at 5000 mg/kg body weight, which is one-hundred and ten times the maximum recommended dose for an adult human. Further research shows no deaths in rats at the same concentration, which equates four hundred times the recommended dose in an adult human.
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.
Mechanism of action
Fexofenadine is a second-generation selectively peripheral H1-blocker of the GI tract, large blood vessels, and bronchial smooth muscle. Blockage prevents the activation of the H1 receptors by histamine, preventing the symptoms associated with allergies from occurring. Fexofenadine cannot cross the blood-brain barrier and therefore does not cause drowsiness. It also exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic, or beta-adrenergic-receptor-blocking effects.
Pharmacokinetics
After oral application, about one-third of the drug is absorbed into the bloodstream. Maximum plasma concentrations are reached after one to three hours. Fexofenadine is effective from one hour to 24 hours after application, with maximum effectiveness after six hours.
Only a small percentage is metabolized in the liver, mainly to the methyl ester and to azacyclonol; both are pharmacologically irrelevant. Most of the substance is eliminated unchanged via the feces (80%) and urine (11–12%).
Interactions
Erythromycin and ketoconazole increase the plasma levels of fexofenadine two- to threefold without influencing the QT interval. The reason for this effect is not well understood and could be caused by increased absorption or reduced gastrointestinal or biliary secretion.
Antacids containing aluminium or magnesium reduce the absorption of fexofenadine. Fexofenadine is not to be taken with fruit juices, as decrease of the absorption of the drug could be effected. Grapefruit juices can significantly reduce plasma concentration of fexofenadine.
While St. John's Wort (hypericum perforatum) and its preparations do interact with fexofenadine, since fexofenadine is a P-glycoprotein substrate and hypericum is an inducer, this interaction is deemed "unlikely to cause problems" - see St John's Wort Interactions table.
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. 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 Food and Drug Administration (FDA) in 1996. 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 $1.87B USD in 2004 (with $1.49B USD coming from the United States). AMRI received royalty payments from Aventis that enabled the growth of AMRI.
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.
Synthesis
Fexofenadine may be synthesized as shown from piperidine-4-carboxylate ester and 4-bromophenylacetonitrile.
To produce the piperidine piece, two phenyl groups are first introduced using a Grignard reaction on the ester, giving a tertiary alcohol. The amine group is then alkylated with a protected aldehyde, then the aldehyde is recovered by deprotection with acid. The remaining piece of the molecule is produced by a double alkylation by iodomethane of the carbanion derived from the nitrile. The nitrile group is then hydrolyzed to a carboxylic acid. The aryl bromide is then lithiated to produce the organolithium compound, which can be coupled with the aldehyde piece to give (after workup) fexofenadine.
References
- Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Houston B, Oosterhuis B, Bjerrum OJ, Rowland M, Garner C (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.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16556272, please use {{cite journal}} with
|pmid=16556272instead. - Dicpinigaitis PV, Gayle YE (2003). "Effect of the second-generation antihistamine, fexofenadine, on cough reflex sensitivity and pulmonary function". British journal of clinical pharmacology. 56 (5): 501–4. doi:10.1046/j.1365-2125.2003.01902.x. PMC 1884387. PMID 14651723.
{{cite journal}}: Unknown parameter|month=ignored (help) - Vena GA, Cassano N, Filieri M, Filotico R, D'Argento V, Coviello C (2002). "Fexofenadine in chronic idiopathic urticaria: a clinical and immunohistochemical evaluation". Int J Immunopathol Pharmacol. 15 (3): 217–24. PMID 12575922.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - March 22, 2011 (2002-11-07). "fexofenadine (Allegra) - drug class, medical uses, medication side effects, and drug interactions by". Medicinenet.com. Retrieved 2011-03-22.
{{cite web}}: CS1 maint: numeric names: authors list (link) - ^ Haberfeld, H, ed. (2010). Austria-Codex (in German) (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
- ^ Dinnendahl, V, Fricke, U, ed. (2010). Arzneistoff-Profile (in German). Vol. 2 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-98-46-3.
{{cite book}}: CS1 maint: multiple names: editors list (link) - ^ Allegra (fexofenadine hydrochloride) tablets, ODT, and oral suspension package insert. Bridgewater, NJ: Sanofi-Aventis; 2008 Dec.
- Allegra D-12 Hour (fexofenadine hcl and pseudoephedrine hcl) tablets, extended release package insert. Bridgewater, NJ: Sanofi-Aventis; 2009 Dec.
- Allegra-D 24 Hour (fexofenadine hcl and pseudoephedrine hcl) tablets, extended release package insert. Bridgewater, NJ: Sanofi-Aventis; 2009 Dec.
- "Fexofenadine", DrugBank, accessed June 13, 2011.
- Klopp, T, ed. (2010). Arzneimittel-Interaktionen (in German) (2010/2011 ed.). Arbeitsgemeinschaft für Pharmazeutische Information. ISBN 978-3-85200-207-1.
- Kamath, AV; Yao, M; Zhang, Y; Chong, S (2005). "Effect of fruit juices on the oral bioavailability of fexofenadine in rats". Journal of pharmaceutical sciences. 94 (2): 233–9. doi:10.1002/jps.20231. PMID 15570603.
- ^ Daniel Lednicer (1999). The Organic Chemistry of Drug Synthesis. Vol. 6. New York: Wiley Interscience. pp. 38–40. ISBN 0-471-24510-0. Cite error: The named reference "Lednicer1999" was defined multiple times with different content (see the help page).
- "Allegra | FAQs". Sanofi-Aventis. Retrieved 5 July 2011.
- Kawai, SH; Hambalek, RJ; Just, G (1994). "A facile synthesis of an oxidation product of terfenadine". J. Org. Chem. 59 (9): 2620–22. doi:10.1021/jo00088a056.
{{cite journal}}: Unknown parameter|month=ignored (help)
- Biological effects: Rampe, D; Wible, B; Brown, AM; Dage, RC (1993). "Effects of terfenadine and its metabolites on a delayed rectifier K+ channel cloned from human heart". Mol. Pharmacol. 44 (6): 1240–5. PMID 8264561.
{{cite journal}}: Unknown parameter|month=ignored (help)
External links
- Fexofenadine (UK patient information leaflet)
- Allegra (Fexofenadine Hydrochloride) label and research information
- "fexofenadine" at medicinenet.com