Evaluation of the efficacy and safety of fexofenadine in the management of chronic idiopathic urticaria: A prospective study with 512 patients

Introduction

Chronic idiopathic urticaria (CIU) is defined as occurrence of urticarial wheals or hives daily or almost everyday lasting for more than 6 weeks.[1] It affects at least 0.1% of the population. The entity covers 75% of the cases of chronic urticaria where the aetiology remains unknown.[2] About 50% of the patients with CIU have concurrent angioedema. The disease occurs most often in the adults and is about twice as common in women as in men.[3] Although the itching/discomfort associated with CIU is not life threatening, it can be incapacitating and may reduce the quality of life for the sufferers resulting in considerable anxiety and depression.[4] Recent research has suggested that patients with CIU finds the outcome of the disease as devastating as those experienced by patients with coronary heart disease.[4]

The pathogenesis of CIU in most of the cases remains unknown. However, recently there have been significant developments in understanding of the disease. At least 25% of the patients with CIU (type 1 urticaria) have circulating IgG autoantibodies against the ? - sub unit of the affinity IgE receptor (FcE Rl?) which is located on the outer surface of mast cells and basophils.[5] These IgG autoantibodies crosslink with Fc8Rla receptors which trigger the release of histamine and other inflammatory mediators resulting in wheals. There is also a small minority of patients with CIU who have IgG anti IgE autoantibodies (type 1A urticaria). It has been found that nearly 60% of the patients with CIU have functional IgG anti FcaRIE autoantibodies.[6] A further subgroup of patients with CIU (approx. 12%) have a mast cell specific circulating factor (type 2 urticaria) which is currently been characterized by Prof Malcom W Greaves′ group. This is a protein, not an immunoglobulin, that does not react with the FcE Rla receptor but promotes the release of histamine from the mast cells. Therefore, the treatment with antihistamines has been the mainstay for patients with mild to moderately severe CIU.[1].[7],[8],[9] It has been proposed that in CIU larger doses of antihistamines may be required than those for the treatment of seasonal allergic rhinitis (SAR).[9]

Fexofenadine, a metabolite of terfenadine, is a recently approved second generation antihistamine with selective peripheral H1 receptor antagonist activity.[10] The drug appears to be quite promising one among the newer antihistamines since it fulfills almost all the criteria for an ideal H1 antagonist viz., rapid onset of action, 24 hour duration of action, rapid onset of action and absence of tachyphylaxis.[10],[11] Moreover, the drug does not cross the blood brain barrier and is devoid of any CNS toxicity. It does not impair cognitive and psychomotor functions.[12] The drug has shown an excellent cardiological safety in clinical trials.[12],[13] This has been in keeping with the result of in vitro studies using the ventricular myocyte model where it did not affect the delayed rectifier potassium channel.[14] Fexofenadine can be taken with ketoconazole or erythromycin without any increase in QTC period.[15]

The present prospective study was undertaken to evaluate the efficacy and safety of fexofenadine in the treatment of CIU at a single daily dosage of 180mg for 6 weeks.

Materials and Methods

The study included 512 patients in whom the diagnosis of CIU was made on the basis of urticarial lesions on at least 3 days a week for the previous 6 consecutive weeks immediately prior to the study. Patients with predominantly physical urticarias and urticarial vasculitis were excluded from the study. Patients known to be hypersensitive to terfenadine were also excluded from the study. Each patient was given fexofenadine 180 mg in a single daily oral dose 1 hour before food at a consistent time each day for a period of 6 weeks. No other systemic or topical medication likely to influence CIU was permitted. The assessment of efficacy and safety was undertaken daily by the patients and the results were recorded in a diary. The investigators (SD, SM, AD) performed the evaluation at 2,4 and 6 weeks. In all patients through cardiological check up and electrocardiogram (ECG) were carried out by the cardiologists (DB, PKH, GM). The patients were asked to record severity of itching experienced in previous 24 hours of medication using rating scale commonly used for the evaluation of CIU viz., a scale of 0 to 4 (where 0= none, 1 = 1-5, 2=6-15,3= 16-25and4= 17-25).[16],[17] The mean daily total symptom score (TSS) was measured as sum of the patients pruritus and number of wheal scores (rating 0-7). A mean TSS was also determined for each week. A patient was considered to have improved if the mean TSS on treatment was less than the mean baseline TSS. The number of patients with ′O′ TSS at every week were recorded. The patients were asked to note the adverse effects if any and report those to the corresponding investigator. Routine haematological examination and urinalysis were performed in each patient.

Results

Of 512, 14 (2.73%) patients dropped out from the follow -up. [Table - 1] highlights the age and sex distributions of the patients. Maximum number of patients were between 20 to 40 year of age and females outnumbered males with a female to male ratio I. 46:1.

[Table - 2] depicts the baseline TSS and weekly reduction of TSS with fexofenadine. The baseline TSS came down to ′O′ by 4 weeks in all groups except those with TSS 4, where in 6 and 2 patients baseline TSS came down to ′0′ after 5 weeks and 6 weeks respectively. However, there was no correlation between the baseline TSS and degree of improvement. While in some patients baseline TSS came down to 0 quickly, in others it took several weeks to respond. There was no report of fexofenadine induced drowsiness or cardiac arrhythmia. The commonest adverse effect was headache (9.04%). Other minor side effects have been listed in [Table - 3]. However, in none of the patients fexofenadine had to be withdrawn because of its toxicity.

Discussion

In the study majority of the patients were between 20 to 40 years of age and females outnumbered males. This was in corroboration with the earlier observations that CIU mostly affects adults and females.[3] There was improvement in TSS in all the patients. The baseline TSS came down to ′0′ by the end of 4 weeks. However, there was no correlation between the baseline TSS and degree of improvement.

The most distressing symptom of CIU is pruritus. It is generally recognized that H1 receptor antagonists are more effective in controlling the pruritus than the whealing.[7] In the present study the drug controlled the pruritus effectively in 50% of the patients within 4 weeks and in 8 patients by 6 weeks. This was in corroboration with the study by Paul et al. Fexofenadine was well tolerated throughout the study period. Adverse effects were analysed in 498 patients. Among the side effects, headache was a common complaint experienced by 45 (9.04%) patients. No patient receiving the medicine complained of drowsiness. Intake of the drug was not associated with palpitation and/ or ECG evidence of QT prolongation in any patient. The observations were in corroboration with the study by Paul et al. The safety profile has been found to remain unaltered with differential dosing schedule for the treatment of different conditions viz. seasonal allergic rhinitis (SAR) or CIU.[11] However, for the treatment of CIU, fexofenadine HC1 180 mg/day dose has been recommended.

Recently the issue of cardiological safety of fexofenadine has been blown out of proportion on the basis of a single case report from the Netherlands. However, we as well as others have failed to appreciate any such adverse effect of the drug in large number of patients,[13] even when the drug was given for longterm and in doses 10 - fold than the recommended one. This has been substantiated by experimental work on the effect of fexofenadine on isolated myocyte preparation.[12]

The study, therefore, demonstrates that fexofenadine HC1 at a single daily oral dose of 180mg is an effective nonsedating antihistamine for the treatment of CIU and is devoid of any significant adverse effect including cardiotoxicity. So far there is not much published data available on 180mg fexofenadine molecule. Most of the studies address the efficacy and safety parameters of 120 mg fexofenadine in seasonal allergic rhinitis (SAR). Therefore, inspite of the fact that the present study is an uncontrolled one, it appears to be worthwhile because of its large sample size.