|Systematic (IUPAC) name|
|(±)-4-[1 hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α, α-dimethyl benzeneacetic acid|
|Trade names||Allegra, Axodin|
|Licence data||US FDA:|
|Metabolism||Hepatic (≤5% of dose)|
|Excretion||Feces (~80%) and urine (~10%) as unchanged drug|
|(what is this?)|
Fexofenadine (trade names Allegra, Fexidine, Telfast, Fastofen, Tilfur, Vifas, Telfexo, Allerfexo) is an antihistamine pharmaceutical drug used in the treatment of allergy symptoms, such as hay fever, nasal congestion, and urticaria. It is often said to be a third-generation antihistamine, which means that its effect are limited to the periphery, that is, outside the brain and spinal cord, which is where most antihistamines mediate their sedating effects, hence fexofenadine produces minimal sedation.
Fexofenadine is used for relief from physical symptoms associated with seasonal allergic rhinitis and for treatment of chronic urticaria. It does not cure but rather prevents the aggravation of rhinitis and urticaria and reduces the severity of the symptoms associated with those conditions, providing relief from repeated sneezing, runny nose, itchy eyes and general body fatigue.
- Renal Impairment: Due to decreased renal elimination in patients with creatinine clearance of less than 80mL/min, it is recommended that patients with renal impairment are started on a lower dose.
- Hepatic Impairment: Perhaps because only a small percentage of fexofenadine is metabolized in the liver, altered levels of drug are not seen in patients with hepatic impairment and therefore doses do not need to be adjusted in this population.
The most common side effects demonstrated in adults were headache, back pain, miosis or pinpoint pupils, drowsiness, and menstrual cramps. There have also been reports of anxiety and insomnia. 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.
Additionally, the half-life of fexofenadine is shorter than cetirizine, so it often must be taken twice daily. However, there is also evidence that cetirizine causes more sleepiness than fexofenadine.
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. 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 one-hundred and ten times (110x) the maximum recommended dose for an adult human. If overdose were to occur, likely seen as dizziness, dry mouth, and/or drowsiness, supportive measures are recommended. It does not appear that hemodialysis is an effective mode to remove fexofenadine from the blood.
Mechanism of action
Fexofenadine is a second-generation selectively peripheral H1-blocker. 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 and is therefore unlikely to cause drowsiness. It also exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic, or beta-adrenergic-receptor-blocking effects.
Absorption: After oral application, maximum plasma concentrations are reached after two to three hours. Fexofenadine should not be taken with a high fat meal, as mean concentrations of fexofenadine in the bloodstream is seen to be reduced from 20-60% depending on form of medication (tablet, ODT, or suspension).
Distribution: Fexofenadine is 60-70% bound to plasma proteins, mostly albumin.
Metabolism: Only a 5% is metabolized in the liver.
Elimination: Most of the substance is eliminated unchanged via the feces (80%) and urine (11–12%).
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 to do transport-related effects, specifically involving p-glycoprotein.
Fexofenadine is not to be taken with apple, orange, or grapefruit juice because it could decrease absorption of the drug and should therefore be taken with water. Grapefruit juice can significantly reduce the plasma concentration of fexofenadine.
Fexofenadine is a pregnancy category C and should be used if the benefits outweigh the risks.
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.
No sufficient studies have been done in patients over age 65. Therefore, it is advised that elderly patients use caution when using fexofenadine, particularly when there is concern for renal impairment.
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. 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 $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.
Fexofenadine is synthesized in convergent fashion (as shown below) from ethyl piperidine-4-carboxylate and 4-bromophenylacetonitrile.
In the synthesis of fexofenadine, the ultimate and critical bond-formation is the addition of a para-substituted aryl lithium species to a gamma-amino-aldehyde. Ethyl piperidine-4-carboxylate is treated with excess phenylmagnesium bromide to afford (4-piperidinyl)diphenylmethanol. Alkylation of the secondary amine using 2-(3-bromopropyl)-1,3-dioxolane and followed by hydrolysis of the acetal, provides 4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanal.
Separately, 2,2-dimethyl-(p-bromophenyl)acetic acid, prepared in two steps from p-bromophenylacetonitrile, is first deprotonated with NaH and then subjected to lithium halogen exchange, using BuLi to provide the intermediate 2,2-dimethyl-(p-lithiophenyl)acetate salt. This aryl lithium reagent is then reacted with the aforementioned butanal derivative to afford fexofenadine after aqueous workup.
- According to Contemporary Drug Synthesis (2004), a number of routes exist for the creation of this compound, not just the original synthesis outlined by Lednicer. For example, the McGill synthesis of Fexofenadine involving a Sonogashira coupling.
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- Allegra (fexofenadine hydrochloride) tablets, ODT, and oral suspension package insert. Sanofi-Aventis; 2007.
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- Daniel Lednicer (1999). The Organic Chemistry of Drug Synthesis 6. New York: Wiley Interscience. pp. 38–40. ISBN 0-471-24510-0.
- "Allegra | FAQs". Sanofi-Aventis. Retrieved 5 July 2011.
- Kawai, Stephen H. (1994). "A Facile Synthesis of an Oxidation Product of Terfenadine". The Journal of Organic Chemistry 59 (9): 2620–2622. doi:10.1021/jo00088a056.
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- Fexofenadine (UK patient information leaflet)
- Allegra (Fexofenadine Hydrochloride) label and research information
- "fexofenadine" at medicinenet.com
- Official website for Allegra brand Fexofenadine