Terfenadine

Terfenadine
Systematic (IUPAC) name
(RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}-butan-1-ol
Clinical data
Trade names Seldane, Triludan, Teldane
AHFS/Drugs.com Multum Consumer Information
MedlinePlus a600034
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Legal status
  • Withdrawn
Pharmacokinetic data
Protein binding 70%
Biological half-life 3.5 hours
Identifiers
CAS Number 50679-08-8 YesY
ATC code R06AX12 (WHO)
PubChem CID 5405
IUPHAR/BPS 2608
DrugBank DB00342 YesY
ChemSpider 5212 YesY
UNII 7BA5G9Y06Q YesY
KEGG D00521 YesY
ChEMBL CHEMBL17157 YesY
Chemical data
Formula C32H41NO2
Molar mass 471.673 g/mol
Chirality Racemic mixture
 NYesY (what is this?)  (verify)

Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi-Aventis) and was marketed under various brand names, including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia.[1] It was superseded by fexofenadine in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart (specifically cardiac arrhythmia caused by QT interval prolongation) and has been withdrawn from markets worldwide.[2]:53

Terfenadine is a prodrug, generally completely metabolized to the active form fexofenadine in the liver by the enzyme cytochrome P450 3A4. Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally is not measurable in the plasma. Terfenadine itself, however, is cardiotoxic at higher doses, while its major active metabolite is not. Terfenadine, in addition to its antihistamine effects, also acts as a potassium channel blocker (Kv11.1 encoded by the gene hERG). Since its active metabolite is not a potassium channel blocker, no cardiotoxicity is associated with fexofenadine.[3] Toxicity is possible after years of continued use with no previous problems as a result of an interaction with other medications such as erythromycin, or foods such as grapefruit. The addition of, or dosage change in, these CYP3A4 inhibitors makes it harder for the body to metabolize and remove terfenadine. In larger plasma concentrations, it may lead to toxic effects on the heart's rhythm (e.g. ventricular tachycardia and torsades de pointes).

History

In the United States, Seldane was brought to market in 1985 as the first nonsedating antihistamine for the treatment of allergic rhinitis.[1][4] In June 1990, evidence of serious ventricular arrhythmias among those taking Seldane prompted the FDA to issue a report on the risk factors associated with concomitant use of the drug with macrolide antibiotics and ketoconazole.[1] Two months later, the FDA required the manufacturer to send a letter to all physicians, alerting them to the problem; in July 1992, the existing precautions were elevated to a black box warning[1] and the issue attracted mass media attention in reports that people with liver disease or who took ketoconazole, an antifungal agent, or the antibiotic erythromycin, could suffer cardiac arrhythmia if they also took Seldane.[4]

In January 1997, the same month when the U.S. Food and Drug Administration (FDA) had earlier approved a generic version of Seldane made by IVAX Corporation of Miami, the FDA recommended terfenadine-containing drugs be removed from the market and physicians consider alternative medications for their patients.[4] Seldane (and Seldane-D, terfenadine combined with the decongestant pseudoephedrine) were removed from the U.S. market by their manufacturer in late 1997 after the FDA approval of Allegra-D (fexofenadine/pseudoephedrine).[5] Terfenadine-containing drugs were subsequently removed from the Canadian market in 1999,[6] and are no longer available for prescription in the UK.[7]

See also

References

  1. 1 2 3 4 Thompson, David; Oster, Gerry (1996). "Use of Terfenadine and Contraindicated Drugs". Journal of the American Medical Association (American Medical Association) 275 (17): 1339–1341. doi:10.1001/jama.275.17.1339. ISSN 0098-7484. Retrieved 2010-11-11.
  2. ↑ Horak F. Antialergic and Vasoactive Drugs for Allergic Rhinitis. Chapter 4 in Allergy Frontiers:Therapy and Prevention. Volume 5 of Allergy Frontiers. Eds Pawankar R et al Springer Science & Business Media, 2010 ISBN 9784431993629
  3. ↑ Roy, Mary-Louise; Brown, Arthur (1996). "HERG, a Primary Human Ventricular Target of the Nonsedating Antihistamine Terfenadine". Circulation (American Heart Association) 94 (4): 817–823. doi:10.1161/01.cir.94.4.817. Retrieved 2014-01-27.
  4. 1 2 3 Harry F. Rosenthal (AP) (January 14, 1997). "FDA May Pull Plug on Seldane". Los Angeles Daily News. TheFreeLibrary.com. Retrieved 2010-11-11.
  5. ↑ "FDA Approves Allegra-D, Manufacturer To Withdraw Seldane From Marketplace". Food and Drug Administration. Archived from the original on 2008-02-23. Retrieved 2010-11-11.
  6. ↑ Status of Terfenadine-Containing Drugs in Canada from Health Canada
  7. ↑ Terfenadine- General Practice notebook from GPnotebook.co.uk

External links

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