Terfenadine
Encyclopedia
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 marketed under various brand names including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia. According to its manufacturer, terfenadine had been used by over 100 million patients worldwide as of 1990. It was superseded by fexofenadine
in the 1990s due to the risk of cardiac arrhythmia
caused by QT interval
prolongation.
Terfenadine is a prodrug
, generally completely metabolised to the active form fexofenadine
in the liver by the enzyme cytochrome P450 CYP3A4
isoform.
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. 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 like 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, terfenadine may lead to toxic effects on the heart's rhythm (e.g. ventricular tachycardia
and torsades de pointes
).
. In June 1990, evidence of serious ventricular arrhythmias among those taking Seldane prompted the FDA to issue a report on the risk factor
s associated with concomitant use of the drug with macrolide
antibiotics and ketoconazole
. 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
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.
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 that terfenadine-containing drugs be removed from the market and that physicians consider alternative medications for their patients. 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). Terfenadine-containing drugs were subsequently removed from the Canadian market in 1999, and are no longer available for prescription in the UK.
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
formerly used for the treatment of allergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
) and marketed under various brand names including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia. According to its manufacturer, terfenadine had been used by over 100 million patients worldwide as of 1990. It was superseded by fexofenadine
Fexofenadine
Fexofenadine is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms...
in the 1990s due to the risk of cardiac arrhythmia
Cardiac dysrhythmia
Cardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
caused by QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
prolongation.
Terfenadine is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, generally completely metabolised to the active form fexofenadine
Fexofenadine
Fexofenadine is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms...
in the liver by the enzyme cytochrome P450 CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
isoform.
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. Toxicity is possible after years of continued use with no previous problems as a result of an interaction with other medications such as erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, or foods like 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, terfenadine may lead to toxic effects on the heart's rhythm (e.g. ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
and torsades de pointes
Torsades de pointes
Torsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation...
).
History
In the United States, Seldane was brought to market in 1985 as the first non-sedating antihistamine for the treatment of allergic rhinitisAllergic rhinitis
Allergic rhinitis, also known as pollenosis or hay fever, is an allergic inflammation of the nasal airways.It occurs when an allergen, such as pollen, dust or animal dander is inhaled by an individual with a sensitized immune system...
. In June 1990, evidence of serious ventricular arrhythmias among those taking Seldane prompted the FDA to issue a report on the risk factor
Risk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...
s associated with concomitant use of the drug with macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
antibiotics and ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
. 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
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
and the issue attracted mass media attention in reports that people with liver disease or who took ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, an antifungal agent, or the antibiotic erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, could suffer cardiac arrhythmia
Cardiac dysrhythmia
Cardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
if they also took Seldane.
In January 1997, the same month when the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) had earlier approved a generic version of Seldane made by IVAX Corporation
Ivax Corporation
IVAX Corporation was a Miami, Florida, United States public corporation focused on manufacturing and distributing generic pharmaceutical products.-History:...
of Miami, the FDA recommended that terfenadine-containing drugs be removed from the market and that physicians consider alternative medications for their patients. Seldane (and Seldane-D, terfenadine combined with the decongestant pseudoephedrine
Pseudoephedrine
Pseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
) were removed from the U.S. market by their manufacturer in late 1997 after the FDA approval of Allegra-D (fexofenadine/pseudoephedrine). Terfenadine-containing drugs were subsequently removed from the Canadian market in 1999, and are no longer available for prescription in the UK.
External links
- Hoechst Marion Roussel Committed to Education Regarding Seldane Usage, an April 30, 1996 press release