Terfenadine: withdrawn second-generation antihistamine
Terfenadine was one of the first H1 antihistamines of the so-called second generation, a class with reduced central nervous activity and therefore less sedative profile than older H1 blockers like diphenhydramine or clemastine. It was launched in 1985 (Triludan, Seldane) and quickly became the world's best-selling non-sedating antihistamine.
In 1998 in the USA and 2001 in the EU terfenadine was withdrawn from the market after several cases of torsade de pointes with sometimes fatal outcome. The cause was marked QT prolongation, especially with CYP3A4 inhibitors such as erythromycin or ketoconazole. This experience contributed decisively to the regulatory requirement for systematic QT investigation of new substances (ICH E14 guideline).
Mechanism of action
Terfenadine itself is a prodrug. Only the active metabolite fexofenadine exerts the antihistaminic effect via H1 receptor antagonism. Blocking H1 receptors reduces classic allergic symptoms such as itching, sneezing, vascular permeability and bronchoconstriction.
Terfenadine itself, however, is a potent inhibitor of the hERG potassium channel (Kv11.1), which mediates cardiac repolarisation. Under normal pharmacokinetics, terfenadine is rapidly converted to fexofenadine and parent levels remain low. With reduced CYP3A4 activity (genetics, interactions, liver disease) terfenadine accumulates, which can cause QT prolongation and torsade de pointes.
This insight prompted introduction of fexofenadine as a pure active metabolite as a stand-alone substance. Fexofenadine (Telfast, Allegra) has the same antihistaminic profile without the cardiac risk of the parent.
Indications
Since terfenadine is no longer marketed in the EU and most countries, today's relevance is limited to historical context and as a textbook example of translational medicine and drug safety. Former indications were:
- Seasonal and perennial allergic rhinitis
- Chronic idiopathic urticaria
- Allergic conjunctivitis
- Atopic dermatitis as symptomatic adjunct
Today, non-sedating second-generation H1 antihistamines are used: fexofenadine, loratadine, desloratadine, levocetirizine or cetirizine.
Dosing and administration
There is no current dosing recommendation, since terfenadine is no longer in trade. Historically, the substance was used at 60 mg twice daily or 120 mg once daily (sustained-release), with water, regardless of meals.
Today the only sensible recommendation: anyone with leftover terfenadine should dispose of it at a pharmacy. Use is not recommended, especially not with other medications, grapefruit juice or liver disease.
Side effects
Common (when on the market): fatigue (paradoxically despite non-sedating classification), dry mouth, dizziness, nausea.
Uncommon: headache, gastrointestinal complaints, rash.
Rare and potentially fatal: QT prolongation with torsade de pointes, ventricular fibrillation, syncope, sudden cardiac death, especially with CYP3A4 inhibitors or QT-prolonging drugs.
The unfavourable risk profile and availability of a safe alternative (fexofenadine) led to the worldwide withdrawal. Today, terfenadine is an example of the importance of pharmacological safety research and post-approval pharmacovigilance.
Interactions
Clinically relevant interactions that led to life-threatening events were:
- CYP3A4 inhibitors: itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, diltiazem, verapamil, grapefruit juice
- QT-prolonging substances: class 1a or 3 antiarrhythmics, antipsychotics, methadone
- Liver disease: reduced CYP3A4 activity, accumulation of parent substance
Special considerations
Status: terfenadine has not been on the market in Germany, the EU and most other countries since the early 2000s.
Leftovers: old packs should be disposed of properly at a pharmacy, not in household waste or wastewater.
Alternative therapies: fexofenadine as a safe successor is available in pharmacies (prescription or OTC depending on strength). Other modern H1 antihistamines are also suitable.
Lessons learned: terfenadine today exemplifies the necessity of thorough cardiac safety investigation, the importance of CYP enzyme interaction analyses and active post-marketing pharmacovigilance. From these experiences international guidelines such as ICH E14 were developed.
Patient communication: those who used to tolerate terfenadine well can switch easily to fexofenadine today. The mode of action is nearly identical, the safety profile clearly better. With chronic allergies, medical advice on choosing the right antihistamine makes sense.
Related substances
- Fexofenadin, the active metabolite as safe successor
- Fexofenadine, English spelling
- Levocetirizine, modern H1 antihistamine
- Triprolidine, classic first-generation H1 antihistamine
- Cinnarizine, H1 antihistamine with anti-vertigo properties
Frequently asked questions
Why was terfenadine withdrawn?
Because of rare but life-threatening cardiac arrhythmias (torsade de pointes), especially in patients on CYP3A4 inhibitors or with liver disease. With fexofenadine as a safe successor available, withdrawal was justifiable.
What alternative is available?
Fexofenadine is the direct active metabolite of terfenadine and has a nearly identical profile without the cardiac risk. It is approved in Germany and available without prescription in many countries. Loratadine, desloratadine and levocetirizine are also modern options.
Are all second-generation antihistamines cardiac concerns?
No. After the experiences with terfenadine and astemizole, all subsequent second-generation antihistamines were systematically tested for QT effects. Loratadine, cetirizine, levocetirizine, fexofenadine and desloratadine are considered cardiac safe.
What about old terfenadine tablets at home?
Do not take them, dispose of them at a pharmacy. Pharmacies take back expired or unneeded medication free of charge and ensure proper disposal.
Sources
- EMA European Medicines Agency
- BfArM Federal Institute for Drugs and Medical Devices
- FDA US Food and Drug Administration
- Gelbe Liste terfenadine monograph
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