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Despite its problems, terfenadine did set a new standard for hay fever treatment

In this article on landmark drugs, Jenny Bryan takes a look at how terfenadine, although not in use today, paved the way for research into non-sedating antihistamines

By Jenny Bryan

In this article on landmark drugs, Jenny Bryan takes a look at how terfenadine, although not in use today, paved the way for research into non-sedating antihistamines

Famous today for the fact that 100 million people used it before its risks were fully recognised, the first non-sedating antihistamine, terfenadine (Triludan), nevertheless set a new standard for the treatment of allergic rhinitis when it was launched by Merrell Dow (now part of Sanofi Aventis) in 1980. Before the introduction of terfenadine, people with hay fever either put up with the sedation and psychomotor retardation of first generation antihistamines, such as chlorphenamine or diphenhydramine, or suffered — usually less than silently. 

“Terfenadine was a godsend when it was introduced because, for the first time, we could offer patients something that would relieve their itchy, runny nose and sneezing, without making them sleepy,” recalls Glenis Scadding, consultant physician at the Royal National Throat, Nose and Ear Hospital, London.

She explains that, at the time when terfenadine was introduced, there was a lot of resistance to using intranasal steroids for allergic rhinitis because of concerns about side effects, especially in children. So antihistamines were the mainstay of treatment, and every summer, teenagers taking “O” and “A” levels had to put up with their hay fever symptoms or risk falling asleep during their examinations.

“What is rather shocking is that, as recently as 2005, research showed that children with seasonal allergic rhinitis who were taking sedating antihistamines were 70 per cent more likely to drop a grade in their exams than children without rhinitis — and that’s in the modern era when non-sedating antihistamines are widely available,” points out Dr Scadding.

Fierce rivalry for non-sedating market

Synthesised in the mid 1970s at Merrell-National Laboratories, terfenadine had a piperidine-based structure used in a wide range of drugs, including haloperidol and some selective serotonin reuptake inhibitors. But successive chemical substitutions eliminated its centrally mediated side effects,1 because neither terfenadine nor its metabolites easily penetrated the blood brain barrier.2 Terfenadine was a prodrug, almost completely metabolised in the liver through cytochrome p450 CYP3A4 to its active metabolite fexofenadine.

Early animal studies showed that, unlike first generation antihistamines, terfenadine lacked central nervous system effects in doses up to 100mg/kg, and dose-related reductions in histamine wheals were reported in healthy volunteers.3 In an early placebo-controlled study of terfenadine and the first generation agent chlorphenamine, significantly more sedation and concentration impairment was seen with chlorphenamine,3 and subsequent studies confirmed the lack of psychomotor effects.4

While Merrell was recording promising results with terfenadine, many other companies were targeting the potentially lucrative non-sedating antihistamine market, including Janssen with astemizole, Schering-Plough with loratadine and UCB with cetirizine. But it was terfenadine that took off first in the UK, and proved so effective and well tolerated that it was subsequently granted over the counter status.

Interactions raise concerns

The first hints of problems with terfenadine began to appear in 1990. US doctors reported a case of torsades de pointes — the polymorphic ventricular tachycardia, associated with a prolonged QT interval — in a patient taking terfenadine with cefaclor, ketoconazole and medroxyprogesterone.5

Serum concentrations of terfenadine were excessive compared with those of its main metabolite and this was attributed to a drug interaction between terfenadine and the p450 3A4 inhibitor ketoconazole. Marion Merrell Dow, by then marketing the product in the UK, wrote to GPs and pharmacists to warn them of the risk of QT prolongation when terfenadine was taken with drugs that inhibited hepatic oxidation, such as ketoconazole and erythromycin.

Further reports gradually accumulated and, in 1992, the Committee on Safety of Medicines (CSM) issued its first warning that terfenadine should not be taken with ketoconazole, erythromycin or drugs with arrhythmogenic potential such as anti-arrhythmic agents and some antidepressants and neuroleptic agents.6 By that time, the CSM had received 94 reports of adverse cardiovascular effects, of which 13 were considered possibly due to the drug’s potential to cause ventricular arrhythmias, including three sudden and three other deaths.6 Nor were the problems limited to terfenadine. In the same warning, the CSM drew attention to 18 reports of cardiovascular problems with astemizole, of which four were ventricular arrhythmias possibly related to prolonged QT interval. Doctors were advised to avoid ketoconazole and erythromycin with this drug as well.

“We were horrified and very surprised about the terfenadine warning,” says Dr Scadding. “There had been some data linking overdoses of astemizole to cardiac problems, but it hadn’t occurred to anyone that problems could arise with terfenadine. It was such a useful drug that we were all using it to treat our rhinitis patients.”

Adverse events continue

Prescribing of terfenadine alongside macrolide antibiotics or ketoconazole decreased following the warnings. A US analysis showed an 84 per cent reduction in same-day dispensing of terfenadine with contraindicated drugs.7 But reports of cardiac adverse events continued to accumulate, and grapefruit juice was added to the list of agents that could adversely interact with terfenadine. By 1997, terfenadine had been linked to 14 deaths in the UK since 1982, and the CSM announced plans to make both terfenadine and astemizole pharmacy only products.8 However, the timely introduction of the active metabolite of terfenadine, fexofenadine (Telfast), by Hoechst Marion Roussel enabled the company to withdraw terfenadine completely. Astemizole was also withdrawn, but loratadine continued to be popular and the introduction of the levo-enantiomer of cetirizine, levocetirizine, gave it a new lease of life too.

Analysis of prescription-event monitoring studies showed that fexofenadine and loratadine were the least-sedating antihistamines and, consequently, they were recommended for people working in jobs where safety was critical.9

“Fexofenadine is probably the least sedating of all the antihistamines, but it has never been as popular as terfenadine. There has also been a change in attitudes to intranasal steroids because we have a generation of products, such as fluticasone and mometasone, with very low systemic bioavailability, so patients are more likely to use them,” Dr Scadding points out.

Current guidelines recommend antihistamines as first line for mild to moderate intermittent and mild persistent rhinitis, and as additional treatment to intranasal steroids in patients with moderate to severe persistent rhinitis that is not controlled by topical steroids alone.10 A meta-analysis of data from over 2,000 subjects with allergic rhinitis in 16 randomised controlled trials showed that intranasal corticosteroids were superior to antihistamines for nasal blockage, nasal discharge, sneezing, nasal itch and postnasal drip. Only nasal discomfort, nasal resistance and eye symptoms were controlled as well with antihistamines as intranasal corticosteroids.11

To Dr Scadding, however, the lasting legacy of terfenadine and the early non-sedating antihistamines was as much their impact on urticaria as on allergic rhinitis: “They made life bearable for patients with allergic rhinitis, but they had a major impact for people plagued by the constant itching of urticaria.  What is disappointing is that, all these years later, so many people still buy sedating antihistamines from their pharmacist. The take home message should be that, whichever antihistamine you choose, make sure it’s non-sedating.”


1 Carr AA, Meyer DR. Synthesis of terfenadine. Arzneimittelforschung 1982;32:1157–9.
2 Woodward JK, Munro NL. Terfenadine, the first non-sedating antihistamine. Arzneimittelforschung 1982;32:1154–6.
3 Kushrestha VK, Gupta PP, Turner P, Wadsworth J. Some clinical pharmacological studies with terfenadine, a new antihistamine drug. British Journal of Clinical Pharmacology 1978;6:25–9.
4 Nicholson AN, Stone BM. Performance studies with the H1-histamine receptor antagonists, astemizole and terfenadine. British Journal of Clinical Pharmacology 1982;13:199–202.
5 Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr. Torsades de pointes occurring in association with terfenadine use. JAMA 1990;264:2788–90.
6 Committee on Safety of Medicines. Ventricular arrhythmias due to terfenadine and astemizole. Current Problems 1992;35:1–2.
7 Thompson D, Oster G. Use of terfenadine and contraindicated drugs. JAMA 1996;275:1339–41.
8 Committee on Safety of Medicines. Current Issues in Pharmacovigilance 1997;23:15–6.
9 Mann RD, Pearce GL, Dunn N, Shakir S. Sedation with “non-sedating” antihistamines: four prescription­event monitoring studies in general practice. BMJ 2000;320:1184–7.
10 Scadding GK, Durham SR, Mirakian R, Jones NS, Leech SC, Farooque S et al. BSACI guidelines for the management of allergic and non-allergic rhinitis. Clinical and Experimental Allergy 2008;38:19–42.
11 Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. BMJ 1998;317:1624–9.

Citation: The Pharmaceutical Journal URI: 11087400

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