Efficacy and central nervous system impairment of newer-generation prescription antihistamines in seasonal allergic rhinitis.

Abstract: Allergic rhinitis is a highly prevalent disorder and oral antihistamines are often used to manage patient symptoms. Older-generation antihistamines, such as diphenhydramine and chlorpheniramine, are effective at relieving the symptoms of seasonal allergic rhinitis (SAR); however, they are associated with adverse events, including sedation and impairment, at, or above, the recommended dose. Newer-generation antihistamines, such as desloratadine, cetirizine and fexofenadine, were developed to minimize adverse events. In this article, studies examining newer-generation antihistamines in adults and children were reviewed. The clinical evidence confirms that desloratadine, cetirizine and fexofenadine are effective at managing the symptoms of SAR in adults and children; however, cetirizine is more likely to cause sedation. Physician intervention is paramount to SAR symptom management. It is essential that appropriate treatment relieves SAR symptoms with absent or minimal adverse events. This is particularly important for those patients involved in skilled and cognitive activities or safety-critical jobs.

Key Words: antihistamine, seasonal allergic rhinitis, desloratadine, cetirizine, fexofenadine

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Allergic rhinitis (AR) is a highly prevalent disorder and is one of the most common diseases encountered by primary care physicians. (1) Currently, it is estimated that more than 50 million Americans suffer seasonally from this common condition (2) and more than 40 million Americans seek annual relief from the bothersome symptoms of AR. (3)

Allergic rhinitis is traditionally subdivided into seasonal AR (SAR) and perennial AR (PAR), based on the time of exposure to allergen and sensitivity. (4) SAR is related to a wide variety of pollen allergens, including wind-pollinated grasses, trees, weeds and spores from fungi, whereas PAR is most frequently caused by dust mites and animal dander (5) or the combination of numerous pollens and molds. Although SAR is often perceived to be a trivial illness, it can result in fatigue, irritability, sleep disorders and cognitive impairment, in addition to local symptoms. Furthermore, if left untreated, SAR can potentially exacerbate and contribute to asthma and sinusitis. (4,6)

As a Type 1 immediate hypersensitivity reaction, SAR is mediated by specific immunoglobulin-E antibodies, which leads to mucosal inflammation, characterized by the symptoms of sneezing, itching, rhinorrhea, nasal blockage and itching of the palate and throat. It is also associated with ocular symptoms, including watery, itchy red eyes. Histamine is the main inflammatory mediator involved in the development of the majority of the symptoms of SAR, and oral antihistamines ([H.sub.1]-receptor antagonists) are considered a mainstay of therapy for alleviating these symptoms. (7) It has been proposed that oral antihistamines are inverse agonists of the [H.sub.1]-receptor, and they act to stabilize the [H.sub.1]-receptor in its inactive conformation. (8)

Traditional first-generation antihistamines, such as chlorpheniramine, diphenhydramine and clemastine, are effective at reducing the symptoms of SAR. Many of these classic antihistamines are currently available over-the-counter (OTC), are relatively inexpensive, and, consequently, are widely used by patients. However, their lack of [H.sub.1]-receptor specificity and propensity to cross the blood-brain barrier can lead to additional unwanted pharmacologic actions such as anticholinergic, antiserotinergic, local anesthetic and [alpha]-adrenergic activity, as well as [H.sub.1]-receptor blockage in the brain. As a result, these agents are associated with a number of unwanted adverse events, (1,4) including dry mouth, tachycardia, urine voiding, and sedation and/or impairment at, or above, the recommended dose. (1,4)

Newer-generation antihistamines, such as loratadine (Claritin), which recently moved from prescription-only to OTC status, desloratadine (Clarinex), cetirizine (Zyrtec) and fexofenadine (Allegra), were developed to minimize the adverse events observed with the earlier agents while maintaining efficacy. In general, the newer-generation agents have improved safety profiles compared with the older antihistamines, with reduced risk of cardiovascular side effects and no incidences of QTc prolongation reported with the currently available agents. (1) Although two antihistamines, terfenadine and astemizole, resulted in QTc prolongation and ventricular arrhythmias, this was not a class effect, and the two agents have been withdrawn from the market in most countries. (4) In terms of central nervous system (CNS) safety, newer-generation agents also have improved profiles over the first-generation agents. (1,4) However, it has been suggested that some newer-generation agents may cause CNS effects at recommended or higher than recommended doses. (1)

Despite the widespread availability of OTC medications, it is important for patients to seek physician advice in assessing their symptoms to obtain a treatment tailored to their individual needs. Such treatment should achieve optimal effectiveness with the most acceptable adverse-event profile. Currently, physicians are faced with a number of antihistamine treatment choices. Clinical efficacy and safety data should be considered when evaluating therapeutic options, thus ensuring that an informed decision can be made when selecting the most appropriate agent for an individual patient. Therefore, the purpose of this review article is to provide primary care physicians with an overview of published efficacy and CNS safety data available on the newer-generation prescription antihistamines to aid in the decision-making process regarding the management of individuals with SAR.

Older-generation Antihistamines

Antihistamines were first discovered by Staub and Bovet (9) at the Louis Pasteur Institute in 1937; the first clinically useful antihistamine, phenbenzamine, became commercially available in the 1940s. (10) During subsequent years, several other antihistamines were developed, which are still in use today, such as diphenhydramine, hydroxyzine and chlorpheniramine. In the United States, diphenhydramine is the most commonly used OTC medication for the treatment of AR. (11) However, as previously mentioned, these classic [H.sub.1]-receptor antagonists are not selective for the [H.sub.1]-receptor site, and they induce a wide variety of dopaminergic, serotonergic and anticholinergic responses. (4)

First-generation antihistamines are used by millions of patients, with and without physician supervision. A recent survey of a random sample of college students revealed that 91.1% of students self-medicated with an OTC product to alleviate allergy symptoms, (12) most of which likely contained a first-generation agent, possibly increasing the risk for an adverse event. In addition, a survey of SAR patients found that more than 54% of individuals self-medicated with OTC treatment, and a third of these patients experienced drowsiness. (13) Furthermore, the issue of over-compliance and polypharmacy with antihistamines may further contribute to the potential for adverse events.

First-generation antihistamines contain aromatic rings and alkyl substitutes that make them lipophilic, explaining their ability to cross the blood-brain barrier, thus causing a variety of unwanted CNS effects, such as sedation and reduced cognitive function (Table). (4) The term 'sedation' not only encompasses drowsiness, but refers to cognitive impairment of specific mental and physical abilities, which can be detrimental to daytime activities, including work and school performance, driving ability and many tasks that require a high degree of concentration and alertness. (4) For example, in studies using specifically developed tests to assess impairment, findings have shown a greater degree of driving impairment in participants receiving diphenhydramine compared with that in participants whose blood alcohol levels were above the legal limit for driving in most states in the US. (14) In contrast, study participants had similar driving performance when treated with fexofenadine HCl 60 mg or placebo. (14) Thus, when prescribing an antihistamine for individuals with SAR, all attributes of an antihistamine should be assessed to prescribe an agent that provides maximum clinical benefit, without interfering with daily living and working activities. (1,15)

Newer-generation Prescription Antihistamines

Assessment of Efficacy The clinical efficacy of antihistamines is evaluated by their ability to provide relief of SAR symptoms, which can be assessed using various artificial models, such as nasal provocation tests, environmental exposure units (EEU) and acute 'day in the park' study designs. Ideally, the clinical efficacy of antihistamines should be evaluated using patients with naturally occurring allergic disease in double-blind, randomized, placebo-controlled clinical trials. More importantly, the appropriate selection and characterization of patients, optimization of the trial design and suitable selection of study endpoints are all central for assessing the clinical efficacy of antihistamines. (16) Patient diary assessments/scores are used to evaluate the clinical efficacy of antihistamines. These include rating scales, such as the total symptom score (TSS), whereby each symptom (eg, sneezing; rhinorrhea; nasal congestion; itchy nose, palate, or throat; and itchy, watery and red eyes) is rated on a 5-point scale (0 = absent, 4 = very severe). Total symptom scores can be assessed either by the patient or physician. In addition, collection of both reflective TSS, an evaluation of symptom severity after a predefined time period, such as 12 hours, and instantaneous TSS, an evaluation of symptom severity immediately before the next dose for the evaluation of treatment effect at trough levels, is recommended by the US Food and Drug Administration to accurately assess the activity of the agent over the entire dosing period.

Efficacy of Newer-generation Agents

Newer- and older-generation antihistamines have similar efficacy profiles. Cetirizine 10 mg, desloratadine 5 mg and fexofenadine HCl 180 mg once daily are three newer-generation prescription antihistamines indicated for use in patients with SAR in the US. To date, a number of pivotal placebo-controlled clinical studies involving large numbers of SAR patients have evaluated the clinical efficacy of cetirizine, desloratadine and fexofenadine. The primary efficacy measure in the majority of these studies has been the assessment of TSS. Using this approach, these studies have consistently demonstrated a statistically significant improvement in TSS when compared with placebo. Fewer 'head-to-head' comparative clinical studies have been performed in patients with SAR. Both placebo-controlled and comparative studies for the three prescription antihistamines will be discussed.

Placebo-controlled Clinical Studies of Cetirizine, Desloratadine and Fexofenadine in Adults and Children with SAR

Several placebo-controlled clinical trials have demonstrated that cetirizine 10 mg once daily is an effective treatment for SAR in adults. (17-19) One such study evaluated the efficacy of several doses of cetirizine (5 mg, 10 mg and 20 mg) in 419 SAR patients. (17) All cetirizine doses were superior to placebo in reducing symptom severity scores for sneezing, rhinorrhea, ocular pruritus, nasal pruritus, watering and redness of the eyes (P < 0.05). In a second study, cetirizine 10 mg was effective in relieving both upper and lower respiratory tract symptoms in patients with SAR and concomitant asthma (n = 186). (18)

Day and colleagues (20,21) conducted two clinical studies using an EEU to characterize the efficacy and onset of action of cetirizine 10 mg, loratadine 10 mg and placebo after patients with SAR were exposed to ragweed pollen in a controlled environment. Cetirizine 10 mg demonstrated an earlier onset of action and was more effective than loratadine 10 mg or placebo at reducing the symptoms of SAR.

Similarly, in the pediatric population, a number of studies have demonstrated that cetirizine is significantly superior to placebo in reducing the severity of SAR symptoms. (22-25) For example, cetirizine 5 mg and 10 mg was examined in a placebo-controlled study in children aged 6 to 11 years with SAR (n = 209). (22) Overall, a significantly greater reduction in TSS was observed over the 4-week treatment period with cetirizine 10 mg compared with placebo (P < 0.05). Reduction in mean weekly symptom scores was also observed with cetirizine 5 mg, but was not statistically different from placebo. No statistically significant improvements in the individual symptom scores of nasal discharge, conjunctivitis and nasal congestion were found with either cetirizine 5 mg or 10 mg compared with placebo. In summary, the findings from these studies have consistently demonstrated that cetirizine 10 mg once daily is an effective treatment for SAR in adults and children.

To date, there are a limited number of published randomized, double-blind, multicenter studies in patients with SAR highlighting the therapeutic benefits of desloratadine 5 mg relative to placebo. (26,27) The first of these publications was a dose-ranging study where the 24-hour efficacy of desloratadine was characterized in more than 1,000 SAR patients. (27) Desloratadine 5 mg to 20 mg once daily was significantly more effective than placebo in improving total morning instantaneous TSS (P < 0.01). In another series of studies carried out during the spring and fall allergy seasons in SAR patients, desloratadine 5 mg once daily was associated with significant improvements in the 12-hour reflective morning/evening TSS over 2 weeks of treatment (P < 0.01 and P = 0.02 for the spring and fall allergy seasons, respectively). (26) Currently, little information is published about the efficacy of desloratadine in pediatric AR patients.

A number of placebo-controlled studies have demonstrated that fexofenadine HCl 120 mg, administered once or twice daily, was superior to placebo in reducing the severity of SAR symptoms. (28-30) For example, Bernstein and colleagues (28) evaluated the clinical efficacy of fexofenadine HCl 60 mg, 120 mg and 240 mg twice daily in the treatment of ragweed SAR. All fexofenadine doses produced statistically significant decreases in reflective TSS from baseline (P [less than or equal to] 0.001 for 60 mg and 240 mg, and P [less than or equal to] 0.01 for 120 mg) when compared with placebo. In addition, all fexofenadine doses were more effective than placebo at reducing the severity of each individual symptom, including nasal congestion (P [less than or equal to] 0.05). Similarly, Bronsky et al (29) compared fexofenadine HCl 40 mg, 60 mg or 120 mg twice daily with placebo in the treatment of fall SAR (n = 1,046). Again, all fexofenadine doses were highly effective at decreasing the 12-hour reflective TSS.

Finally, van Cauwenberge et al (30) compared once-daily fexofenadine HCl 120 mg with loratadine 10 mg and placebo in the treatment of SAR in a multicenter, multinational, double-blind, parallel-group, randomized, placebo-controlled 2-week study (n = 688). Fexofenadine and loratadine were superior to placebo in reducing mean 24-hour reflective TSS from baseline (P [less than or equal to] 0.0001 and P [less than or equal to] 0.001, respectively) (Fig. 1). In addition, fexofenadine and loratadine were superior to placebo in reducing instantaneous TSS (P [less than or equal to] 0.0001 and P [less than or equal to] 0.005, respectively) from baseline, and individual 24-hour reflective symptom score changes for sneezing, rhinorrhea, itchy nose/palate/throat and itchy/watery/red eyes (P [less than or equal to] 0.005 and P [less than or equal to] 0.05 for fexofenadine and loratadine, respectively).

[FIGURE 1 OMITTED]

More recently, in the pediatric population, fexofenadine HCl 30 mg twice daily was evaluated in a large multicenter, multinational study of children aged 6 to 11 years with SAR (n = 935). (31) Fexofenadine showed a statistically significant improvement in the TSS (sum of sneezing; rhinorrhea; itchy nose, palate, throat and/or ears; itchy, watery, and/or red eyes) compared with placebo (P [less than or equal to] 0.0001). In addition, assessment of all the individual symptom scores, including nasal congestion, showed that fexofenadine was statistically significantly better than placebo (P < 0.01) at reducing all symptoms. (31)

Comparative Clinical Efficacy of Cetirizine and Fexofenadine in Adults

As desloratadine was approved for the treatment of SAR in December 2001, there are no known published direct comparisons of desloratadine with cetirizine and fexofenadine. This is in contrast to cetirizine and fexofenadine, where a number of 'head-to-head' comparative clinical trials highlight that both cetirizine 10 mg and fexofenadine HCl 120 mg and 180 mg significantly reduce the symptoms of SAR to a similar degree. (32-34)

The largest of these studies was undertaken to assess the effects of once-daily cetirizine 10 mg and fexofenadine HCl 120 mg and 180 mg in 842 adult SAR patients. (32) The results from this randomized, double-blind, placebo-controlled study demonstrated that both cetirizine 10 mg and fexofenadine HCl 120 mg and 180 mg had comparable efficacy for the reduction of the 24-hour reflective and instantaneous TSS (Fig. 2). More recently, results from a study by Hampel et al (34) demonstrated that once-daily cetirizine 10 mg and fexofenadine HCl 180 mg were equally effective at relieving the symptoms of SAR in 495 patients. In addition, a study using the Vienna Challenge Chamber demonstrated that both cetirizine 10 mg and fexofenadine HCl 120 mg once daily alleviated the symptoms of SAR to a similar degree (n = 40). (33)

[FIGURE 2 OMITTED]

Quality of Life

Health-related quality of life (QoL) is now recognized as an important outcome measure of clinical efficacy; however, this is often still neglected when assessing the efficacy of therapies for SAR. Approximately 90% of SAR patients believe that their work or classroom productivity is negatively affected by their allergy symptoms. (35) Therefore, given the burden of the symptoms of SAR on patients' well being, clinically effective antihistamines should improve patients' QoL. Questionnaires such as the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and the Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) questionnaire, have been developed to assess the impact of SAR symptoms on QoL and work productivity. (36-38)

Placebo-controlled studies in SAR patients have demonstrated that both cetirizine and fexofenadine are associated with significant improvements in health-related QoL. (35,39,40) For example, a recent placebo-controlled study of over 400 SAR patients demonstrated that cetirizine-treated patients (10 mg once daily) had significantly greater improvement in overall health-related QoL compared with the placebo group (P < 0.001). This improvement in QoL was also associated with significant symptom relief. (39) In another study, van Cauwenberge et al (30) assessed the impact of once-daily fexofenadine HCl 120 mg, loratadine 10 mg and placebo (n = 509) on the QoL of patients with SAR. For all treatment groups (fexofenadine, loratadine and placebo), there was a significant improvement from baseline in overall QoL (P < 0.0001); however, the improvement in the fexofenadine group was significantly greater than that obtained in either the loratadine (P [less than or equal to] 0.03, fexofenadine versus loratadine) or placebo (P [less than or equal to] 0.005, fexofenadine versus placebo) groups. Overall, the findings from these controlled clinical studies demonstrate that both cetirizine and fexofenadine are beneficial in improving QoL in patients with SAR, further highlighting the clinical efficacy of these agents.

While there is a lack of published data assessing the potential benefits of desloratadine in improving patients' QoL, preliminary data presented at scientific congresses suggest that desloratadine improves various aspects of QoL. (41,42) Furthermore, recent data have shown that desloratadine 5 mg improves simulated work place performance in patients with SAR. (43)

Central Nervous System Impairment

Newer-generation antihistamines are less impairing than first-generation compounds; however, some newer-generation agents can produce some level of impairment at recommended, or higher than recommended doses (Table 1). In one study, the combined incidence of drowsiness and fatigue was observed to be significantly greater in patients treated with cetirizine than in those treated with fexofenadine (P = 0.018). (32) In addition, once-daily fexofenadine HCl 180 mg produced significantly greater improvements in drowsiness from baseline at each of the three daily time points (7 AM, 10 AM and 3 PM) assessed compared with the cetirizine Group 10 mg (P = 0.0248, 0.0292 and 0.0406, respectively). (34) The fexofenadine-treated group also tended to show greater improvements in overall motivation compared with those given cetirizine (P = 0.0504). (34)

Salmun and colleagues (44) reported that cetirizine produces significantly greater somnolence (10 AM: P = 0.008; 12 PM: P = 0.001; 3 PM: P < 0.001) and reduces motivation (10 AM: P = 0.014; 12 PM: P = 0.001; 3 PM: P < 0.001) at three time points assessed throughout the day compared with loratadine-treated AR patients. Furthermore, the results of a postmarketing surveillance study evaluating the frequency with which sedation was subjectively reported in over 43,000 cases indicated that cetirizine was 3.5 times more likely to result in subjective reports of sedation than loratadine. (45) No significant differences were reported between loratadine and fexofenadine concerning sedation. (45) Similarly, desloratadine does not impair cognition, including sleepiness and psychomotor performance, at the 5 mg recommended dose. (46,47)

However, a meta-analysis revealed that loratadine used at higher than recommended doses impairs digit substitution (a laboratory assessment of speed and accuracy in which subjects are asked to match symbols and numerals in a short time interval) and driving (20 and 40 mg) and increases sleepiness (40 mg). (48) Desloratadine has also been found to increase drowsiness (20 mg) and CNS impairment (10 and 20 mg) at higher than recommended doses when compared with placebo. (49) In addition, somnolence was found to be increased at the highest dose. On average, 3% of patients across the 2.5 to 10 mg groups complained of somnolence compared with 6% in the 20 mg group. (27) Similar effects have not been observed with fexofenadine at higher than recommended doses, up to 360 mg. (50)

Fexofenadine has demonstrated a comparable profile with placebo in recent objective tests of driving performance, even at higher than recommended doses of 240 mg. (14,51-54) In a recent clinical trial, subjects given fexofenadine HCl 120 mg did not show impaired driving compared with placebo when involved in a divided attention task of cellular phone usage and driving. (55) Similarly, in a further study, fexofenadine HCl 180 mg did not impair driving or cognitive and psychomotor performance when combined with alcohol. (53) In contrast, cetirizine produced impaired driving at recommended doses. (56) Furthermore, data suggest that both cetirizine 10 mg and alcohol impair driving and alter electroencephalogram recordings; these effects appeared to be additive when alcohol and cetirizine were combined, compared with cetirizine alone. (57) Similar findings were not observed with loratadine 10 mg. (57) Subjects given desloratadine 5 mg also did not show impaired driving, with similar findings for standard deviation of lateral position (SDLP) when driving and faster brake reaction times compared with placebo (P = 0.033). (58)

Finally, it has been reported that there are populations of individuals who are thought to be slow metabolizers of desloratadine: 7% of the general population and 20% of the African-American population. (59) These individuals have difficulty in converting desloratadine to its active metabolite and are, therefore, more likely to be susceptible to increased blood levels and associated dose-related adverse events. However, further investigations are warranted to assess the clinical risks of prolonged increased desloratadine exposure and the underlying genotypes conferring the different phenotypes for desloratadine pharmacokinetics.

Conclusions

Allergic rhinitis is a highly prevalent disorder and physician intervention is vital for the management of this disease. Oral antihistamines are considered a mainstay treatment based on clinical benefits that have been established over a number of years and their rapid onset of action. It is essential that patients receive a treatment with both therapeutic benefits and good safety profiles. Therefore, when prescribing an antihistamine, it is important to consider not only the medical benefits but also the potential to produce significant side effects, including CNS impairment. This is an important factor for all patients, particularly for those involved in skilled or cognitive activities, or employed in safety-critical jobs, such as pilots and operators of heavy machinery.

Acknowledgment

The authors would like to thank Mara Morr, PhD, for her editoral assistance. Editorial support was funded by sanofiaventis US, Inc.

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Dennis L Spangler, MD, and Stephen Brunton, MD

From the Atlanta Allergy and Asthma Clinic, Atlanta, GA, and the Cabarrus Family Medicine Residency/North East Medical Center, Charlotte, NC.

Reprint requests to Dennis L Spangler, MD, Atlanta Allergy and Asthma Clinic, 1965 N. Park Place, N.W., Atlanta, GA 30339. Email: [e-mail]

Accepted February 15, 2006.

RELATED ARTICLE: Key Points

* Allergic rhinitis is a highly prevalent disorder and one of the most common diseases encountered by primary care physicians.

* First-generation antihistamines are effective at relieving the symptoms of allergic rhinitis, but are associated with several unwanted adverse events.

* The newer-generation prescription antihistamines, desloratadine, cetirizine and fexofenadine, are effective at managing the symptoms of seasonal allergic rhinitis in adults and children, although cetirizine has been shown to be more likely to cause sedation.

* Cetirizine and fexofenadine are equally effective at improving patient quality of life, as observed in placebo-controlled clinical trials.

* Physician intervention is paramount to the management of seasonal allergic rhinitis, and it is essential for patients, particularly those involved in skilled and cognitive activities, to seek advice in assessing their symptoms, to obtain the most appropriate treatment that maximizes clinical benefit without interfering with daily living activities.

Table. Side effects associated with first- and second-generation
antihistamines

                        Sedation/impairment effect
                    Recommended dose  Above recommended dose

First-generation
  Diphenhydramine   +++               +++
  Clemastine        +++               +++
  Chlorpheniramine  ++                ++

Second-generation
  Cetirizine        +                 ++
  Desloratadine     0                 +
  Fexofenadine      0                 0

0, no effect; +, low effect; ++, moderate effect; +++, high effect.