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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names, including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia.^[1] It was superseded by fexofenadine in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart (specifically cardiac arrhythmia caused by QT interval prolongation) and has been withdrawn from markets worldwide.^[2]^:53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 23(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]

References

^ ^a ^b ^c ^d 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.
^ 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
^ 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.
^ ^a ^b ^c Harry F. Rosenthal (AP) (January 14, 1997). "FDA May Pull Plug on Seldane". Los Angeles Daily News. TheFreeLibrary.com. Retrieved 2010-11-11.
^ "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.
^ Status of Terfenadine-Containing Drugs in Canada from Health Canada
^ Terfenadine- General Practice notebook from GPnotebook.co.uk

External links

Hoechst Marion Roussel Committed to Education Regarding Seldane Usage, an April 30, 1996 press release

UpToDate Contents

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1. 後天性ＱＴ延長症候群 acquired long qt syndrome
2. アレルギー性鼻炎の薬物療法 pharmacotherapy of allergic rhinitis
3. 心不全患者において使用をさけるべき、または慎重に使用するべき薬 drugs that should be avoided or used with caution in patients with heart failure
4. QT延長症候群の病態生理 pathophysiology of the long qt syndrome
5. QRS幅の広い頻脈のマネージメントおよび評価 management and evaluation of wide qrs complex tachycardia in children

English Journal

PMID 21586548

Drug-Induced QTC Prolongation Dangerously Underestimates Proarrhythmic Potential: Lessons From Terfenadine.

Hondeghem LM, Dujardin K, Hoffmann P, Dumotier B, De Clerck F.SourceFrom the *Department of Pharmacology, KU Leuven, Leuven, Belgium; †Department of Cardiology, H. Hart Ziekenhuis, Roeselare, Belgium; ‡Novartis Pharmaceuticals Corp, East Hanover NJ; §Safety Pharmacology, Novartis Pharma AG, Basel, Switzerland; and ?PharmaConsulting, Beerse, Belgium.
Journal of cardiovascular pharmacology.2011 May;57(5):589-97.
PMID 21346598

Japanese Journal

Developmental Changes in Action Potential Prolongation by K+-Channel Blockers in Chick Myocardium

Nouchi Hideaki,Kiryu Naoaki,Kimata Mikio,Tsuneoka Yayoi,Hamaguchi Shogo,Namekata Iyuki,Takahara Akira,Shigenobu Koki,Tanaka Hikaru
Journal of Pharmacological Sciences 115(2), 235-238, 2011
… Terfenadine prolonged action potential duration in the 11 – …
NAID 130000439947

Inhibitory Effects of the Methanol Extract of Ganoderma lucidum on Mosquito Allergy–Induced Itch-Associated Responses in Mice

Andoh Tsugunobu,Zhang Qun,Yamamoto Takumi,Tayama Manabu,Hattori Masao,Tanaka Ken,Kuraishi Yasushi
Journal of Pharmacological Sciences advpub(0), 1010060458, 2010
… The scratching was inhibited by the H1 histamine–receptor antagonist azelastine, but not by the peripherally acting H1-antagonist terfenadine, at the oral dose of 30 mg/kg. … Although terfenadine (30 mg/kg) inhibited plasma extravasation induced by ESGM in the sensitized mice, G. …
NAID 130000439885

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リンク元

「テルフェナジン」

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	Withdrawn;
Pharmacokinetic data
Protein binding	70%
Biological half-life	3.5 hours
Identifiers
CAS Number	50679-08-8
ATC code	R06AX12 (WHO)
PubChem	CID 5405
IUPHAR/BPS	2608
DrugBank	DB00342
ChemSpider	5212
UNII	7BA5G9Y06Q
KEGG	D00521
ChEMBL	CHEMBL17157
Chemical data
Formula	C32H41NO2
Molar mass	471.673 g/mol
Chirality	Racemic mixture
	SMILES OC(c1ccccc1)(c2ccccc2)C4CCN(CCCC(O)c3ccc(cc3)C(C)(C)C)CC4 ;
	InChI InChI=1S/C32H41NO2/c1-31(2,3)26-18-16-25(17-19-26)30(34)15-10-22-33-23-20-29 (21-24-33)32(35,27-11-6-4-7-12-27)28-13-8-5-9-14-28/ h4-9,11-14,16-19,29-30,34-35H,10,15,20-24H2,1-3H3 ; Key:GUGOEEXESWIERI-UHFFFAOYSA-N ;
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　　[★]

英: terfenadine
商: トリルダン, Seldane
関: 抗ヒスタミン薬

第二世代ヒスタミン薬
抗アレルギー薬

抗ヒスタミン薬

ピペリジン系

ヒスタミンH₁受容体拮抗作用
化学伝達物質遊離抑制作用
ロイコトリエン拮抗作用
販売停止

副作用

QT延長、心房性不整脈(torsades de pointes)を起こし、心停止を起こしうる
テルフェナジンはプロドラッグであり、99.5%がすぐ代謝されフェキソフェナジンとなる
代謝が滞るとテルフェナジンは電位依存性Kチャネルを抑制するので危険。
テルフェナジン代謝酵素はCYP3A4で代謝されるので、これを阻害する薬物(CYP3A4と親和性の高い薬物)との併用は危険

イトコナゾール、ミコナゾール、抗真菌剤、マクロライド抗生物質、ドセタキセル、パクリタキセル
肝障害、グレープフルーツ

服用に注意を要するのはQT延長をおこしやすい人

[jama96-1] 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

[Cir1996-3] 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.

[ladainews-4] 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

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terfenadine