Medications for Allergy

Overall, intranasal CSs are well tolerated, even by children. All intranasal corticosteroids are currently pregnancy category C. Although budesonide oral inhaler (Pulmicort) is pregnancy category B, budesonide nasal spray remains category C. The side effect profile of these agents derives from clinical studies as reported adverse events, and published case reports. Table 3 lists the most common reactions. The most serious effects that would impact continuing therapy are nose bleeding and nasal septal perforation.

Topical administration of intranasal corticosteroids (CS) does not necessarily translate into a lack of systemic availability or risk of systemic effects. Table 4 lists pharmacokinetic parameters of select intranasal corticosteroids. The newer agents, fluticasone propionate and mometasone furoate, have lower bioavailabilities. Mometasone has the lowest systemic availability with fluticasone following closely. However, differences in bioavailability have not translated well into differing systemic effects. In general, all intranasal corticosteroids have been demonstrated to be safe at FDA recommended dosages.

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Any exogenous glucocorticoid in the body will cause less endogenous glucocorticoid production. In turn, measurements of basal hypothalamic-pituitary-adrenal (HPA) activity provide the most sensitive indication of systemic exposure to intranasal CS. However, presence of exogenous glucocorticoid does not absolutely translate into an increased risk of altered physiologic systems. Such overly sensitive markers include urinary-free cortisol excretion and area-under-the-curve cortisol concentration. To determine whether the bioavailability of intranasal corticosteroids is having an adverse clinical impact, other testing procedures are warranted. The adrenocorticotropic hormone (ACTH) stimulation test has better predictive value than previously mentioned tests of HPA-axis function. Studies that examined various intranasal CS (beclomethasone, budesonide, fluticasone, mometasone, and triamcinolone) showed no significant effect on basal HPA-axis function.

In children, intranasal corticosteroids maintain their efficacy but are associated with concerns of possible effects on growth velocity. As with inhaled corticosteroids, study design was directed on the younger prepubertal child. In a placebo-controlled trial (n=100, age 6 to 9.5 years), beclomethasone was shown to impair growth velocity to a statistically significant degree (0.9 cm over 1 year of treatment). However, as with inhaled corticosteroids, this may appear to be a drug-specific phenomenon. Mometasone furoate (highly potent and extensively cleared compound) has been studied in young children and did not have any adverse impact on their growth rate. These findings are in keeping with studies in asthma using the newer agents that show no sustained effects and ultimate attainment of expected adult height. The FDA is currently in the midst of drafting a document to provide guidance in the design, conduct, and evaluation of clinical studies to assess the effects of intranasal corticosteroids on linear growth. Until more studies are published and study design issues resolved,when using intranasal corticosteroids in children it may be prudent to use the lowest effective dose and monitor growth (especially in high-risk children). Children with concurrent asthma and treated with orally inhaled corticosteroids may be at highest risk.

All aqueous intranasal CS preparations contain preservatives. Benzalkonium chloride is the preservative of choice for beclomethasone, flunisolide, fluticasone, mometasone and triamcinolone. Budesonide contains potassium sorbate as the preservative. In vitro, benzalkonium chloride has cytotoxic effects on epithelium and damages ciliary motility. Klossek et al.evaluated the 6-month treatment effect of Nasacort AQ (aqueous triamcinolone with benzalkonium as preservative) 220 mcg/day in subjects with perennial allergic rhinitis. Nasal biopsies were performed before and after treatment. The study determined that sustained treatment with intranasal triamcinolone did not lead to atrophy of the nasal mucosa or impairment of mucociliary function. In another report, the alcohol component was implicated in slowing ciliary motility. These authors recommend alcohol-free formulations, especially for chronic use. The clinical relevance of this potential adverse effect is likely to be insignificant. Overall, except for the possibility of intranasal beclomethasone, the intranasal corticosteroids have a good safety profile and are well-tolerated.

Intranasal corticosteroids (CS) can prevent symptoms of seasonal allergic rhinitis when initiated prior to the start of the allergy season. In patients with mild intermittent symptoms, oral or intranasal antihistamines provide adequate relief and would remain recommended as first line in this population. Once symptoms become more persistent and bother the patient moderately or greater, intranasal steroids should be prescribed. More recent data suggest the ability of newer potent intranasal CS to achieve onset of clinical benefit comparable to oral antihistamines. Clinical evidence supporting this is provided by a study conducted by Kaszuba et al.In this open-label study, 88 patients with documented clinical ragweed allergy (skin prick positive and symptoms during ragweed season for the previous 2 seasons) were evaluated. Patients were randomized to receive either 2 sprays fluticasone in each nostril once daily or 10 mg loratadine once daily when bothersome symptoms occurred.

Of the 28 potential days patients could take their assigned medication, both groups used their medication for similar durations (17 days in the fluticasone group and 18 days in the loratadine group, p-value not significant). By week 2 (differences detected by day 5) and week 4, patients who took intranasal fluticasone had significantly fewer symptoms and improved quality of life, respectively. In addition, eosinophil counts and eosinophilic cationic protein levels were both significantly decreased compared to loratadine. The rationale for periodic fluticasone use is through fluticasone’s ability to suppress early the inflammatory cells and subsequent activation of the late phase when the patient is exposed to further antigen. However, until more studies are published in support of intermittent use of intranasal corticosteroids, patients should be instructed to use intranasal CS continuously during their allergy season.

The superiority of intranasal steroids over oral antihistamines is reported in a meta-analysis of 16 randomized controlled trials involving 2,267 subjects (mean age 32 years, range 12-75 years) with allergic rhinitis. Studies were excluded if they evaluated nonclinical outcomes such as in vitro results of inflammatory mediators. The intranasal CS used in these studies included beclomethasone, budesonide, fluticasone, and triamcinolone. Oral antihistamines were astemizole, cetirizine, dexchlorpheniramine, loratadine, and terfenadine. Using a fixed effects model, intranasal steroids were significantly better in providing relief in the domains of nasal blockage, postnasal drip, sneezing, and nasal itch. With respect to ocular symptoms, there were no differences between the intranasal steroid and oral antihistamines. The study reported more heterogeneity in the data for the ocular symptoms, highlighting the variability in allergic rhinitis disease expression and the requirement to tailor therapy to individual patients.

More recently, Rinne and colleagues revisited this issue, comparing a newer potent intranasal steroid (budesonide 280 mcg/day) to cetirizine 10 mg qd – a second-generation oral antihistamine considered the most potent and effective of the oral antihistamines. This study is important because it was published after the meta-analysis and contains methodology similar to published asthma studies. Newly diagnosed patients (n=143, 60% diagnosed <2 years) were randomized in a blinded fashion to either budesonide or cetirizine for one year of continuous treatment. A protocol was established to treat patients with intolerable breakthrough symptoms in a step-wise fashion. A unique aspect of this trial was an additional 12-month open-label extension; this phase sought to determine when patients experienced their first relapse after discontinuing therapy. Table 2 summarizes the clinical outcomes of this comparison. There were no significant differences in the occurrence of adverse effects between the two groups. This study concluded that intranasal budesonide is more effective than cetirizine for the long-term treatment of allergic rhinitis.

Allergic rhinitis deserves attention due to its high prevalence in adults and children along with significant associated morbidity. Allergic rhinitis is classified in two main categories: seasonal and perennial. Patients with the seasonal form exhibit acute symptoms during the times of year when pollens are released from trees (early spring), grasses (late spring/early summer), and other plants such as ragweed (late summer and fall). The perennial form includes allergens that are present all year round (animal dander, dust mites, and cockroaches).

The combined (direct and indirect) costs of managing allergic rhinitis have been estimated to range from $3.25 to $8 billion every year. The direct costs include visits to the physician, laboratory testing, medications, and the costs of treating the complications. The indirect costs include loss of income due to absenteeism and costs to businesses from reduced productivity at work.

Allergic rhinitis has been regarded as an annoying disease and the associated complications underappreciated. The untreated inflammatory process in the nose can result in socially embarrassing features, such as the “allergic salute” (running the palm of the hand upward across the nose, leading to a crease across the bridge of the nose), as well as medically significant complications such as asthma, sinusitis, otitis media with effusion, or the development of nasal polyps. Other potential consequences of undertreated allergic rhinitis can include irritability, fatigue, lethargy, poor concentration, and poor self-image.

Patients entering a pharmacy are confronted with a plethora of over-the-counter agents to treat their symptoms. Direct-to-consumer advertising may add to this overwhelming milieu. In 1999, the pharmaceutical industry spent $226 million advertising antihistamines and $114 million advertising intranasal corticosteroids (CS) directly to patients. This accounts for nearly 6% of antihistamine sales and 12% of nasal CS sales. Healthcare providers are equally overwhelmed with the choices of legend drugs available and the pressures they bear from pharmaceutical industry sales representatives. This article will discuss the use of aqueous nasal corticosteroids for the management of allergic rhinitis and emphasize practical issues in their use.

Linking Nasal Inflammation with Clinical Presentation

Patients with allergic rhinitis are believed to have a genetic predisposition for the development of Immunoglobulin E (IgE) antibodies against specific molecules (allergens). The process begins with repeated exposure to the allergen causing a sensitization or priming of the immune system. The immune system is now poised to respond using a complex array of cells and cytokines to initiate the allergic response. Allergic rhinitis is the clinical disease expression of this sensitivity characterized by an acute-phase response and late-phase response.

The acute-phase response is triggered when the allergen interacts with IgE molecules bound to mast cells. There are more mast cells in the noses of allergic individuals than in nonallergic individuals. Mast cells become activated and release preformed mediators of which histamine is the most well known. Accompanying histamine are mediators that are newly synthesized as a result of the allergen-antibody interaction. These synthesized mediators are the products of arachidonic acid metabolism (involving the cyclooxygenase and 5-lipoxygenase enzyme systems) and include potent proinflammatory molecules such as prostaglandins (PG), leukotrienes, and various interleukins. Both groups of preformed and newly synthesized mediators are responsible for the clinical manifestations of allergic rhinitis.

The clinical manifestation of the acute-phase relies on the faster acting of the mediators. Histamine is the primary mediator involved. Approximately half of the symptoms of allergic rhinitis can be attributed to histamine. Clinical manifestations of histamine depend on the binding location within the nose. The nasal turbinates are the target tissue for the allergic cascade. The turbinates are soft tissue appendages inside the nose that help filter and humidify inspired air. When histamine occupies endothelial cells of postcapillary venules, the result is increased vascular permeability leading to mucosal edema (of the turbinates), feelings of congestion, and watery rhinorrhea. Histamine causes itching and sneezing when it binds to nociceptive neurons. These symptoms can often be controlled by H1-antihistamines. Older generations of antihistamines (diphenhydramine and chlorpheniramine) have been notorious for their sedative and drying effects, making patient acceptance low in an era of newer, less sedating antihistamines (fexofenadine and loratadine). The chronic inflammatory process sustains persistent patient symptoms including nasal blockage. In this phase, only a partial response is achieved with antihistamines.The newly formed mediators (PG and leukotrienes) contribute to nasal congestion, rhinorrhea, and edema.

The late-phase reaction is responsible for the ongoing clinical symptoms suffered by the patient. It involves the recruitment of a new host of chemo-attractants, proinflammatory cells (eosinophils) and their highly cytotoxic mediators (major basic protein, eosinophil cationic protein, IL-5, etc). Symptoms in the late phase tend to be similar to those experienced in the acute phase, predominately nasal congestion. The complications of allergic rhinitis are often the result of undertreated chronic mucosal inflammation. To improve symptoms and reduce long-term complications, treatments should target the underlying inflammation.

Topical nasal corticosteroids (CS) gain entry into the cell cytoplasm and interact with the glucocorticoid receptor (GR). The CS/GR complex undergoes a conformational change, becoming active, prior to entering the cell nucleus. Gene expression is hypothesized to be a principal mechanism of altering the inflammatory state. The direct effects may be a reduction in the cytokine-induced production of pro-inflammatory mediators. Whether the interaction has activating or repressive effects may be dependent on the gene being modified. The clinical benefits observed with CS can be attributed to the wide-ranging suppressive effects on the immune system, and anti-inflammatory mediator production. This article will further discuss these clinical benefits by summarizing representative clinical studies evaluating nasal corticosteroids in allergic rhinitis.

The cellular and biochemical effects of glucocorticoids are immediate, but varying times are required to produce a clinical response from corticosteroids. After exposure to the allergic trigger, rhinitis symptoms have a rapid onset, often within minutes. Treatment needs to take effect as quickly, or better still, prevent symptoms from occurring. The traditionally held view was that the onset of clinical effect from intranasal CS was delayed by several days. More recent evidence contradicts this and suggests a quicker onset in benefit. Consequently, most patients’ symptoms will improve within the first 1-2 days of therapy and reach maximum improvement in 1-2 weeks. This is explained by the ability of corticosteroids to attenuate both the acute phase and late phase of the allergic reaction. Nasal challenge studies show a marked decrease in symptoms and inflammatory cells and their products. The clinical presentation of allergic rhinitis is patient-specific and there is variability in how patients present. Table 1 lists the various signs and symptoms of allergic rhinitis, although not all patients will express all symptoms.