Bruce M. Prenner

Long-term safety and efficacy of intranasal ciclesonide in adult and adolescent patients with perennial allergic rhinitis

BACKGROUNDnCiclesonide is a corticosteroid in development for allergic rhinitis that has been shown to be safe and effective in seasonal allergic rhinitis and perennial allergic rhinitis (PAR) trials of up to 6 weeks in duration. However, the long-term safety and efficacy of ciclesonide are unknown.nnnOBJECTIVEnTo demonstrate the long-term safety of intranasal ciclesonide, 200 microg once daily, in patients with PAR.nnnMETHODSnPatients (> or = 12 years old) with a 2-year or longer history of PAR were randomized in a double-blind fashion to receive ciclesonide, 200 microg, or placebo once daily in the morning for up to 52 weeks. Spontaneous and elicited adverse events were monitored throughout the study. Ear, nose, and throat examinations were performed to evaluate local tolerability. Additionally, 24-hour urinary free cortisol level, morning plasma cortisol level, intraocular pressure, and lens opacification were monitored to evaluate the systemic safety of intranasal ciclesonide. Ciclesonide efficacy was determined by measuring 24-hour reflective total nasal symptom scores.nnnRESULTSnNo clinically relevant differences were observed between the ciclesonide and placebo groups in adverse events, ear, nose, and throat examinations, or 24-hour urinary free or morning plasma cortisol levels. Similarly, no clinically relevant differences were found between treatment groups in intraocular pressure, visual acuity, or lens opacification. With regard to efficacy, ciclesonide achieved a significantly greater reduction in 24-hour reflective total nasal symptom score compared with placebo over more than 52 weeks (P < .001).nnnCONCLUSIONnIn this study, intranasal ciclesonide, 200 microg once daily, was safe and effective for the long-term treatment of PAR, with no evidence of tachyphylaxis.

Double-strength beclomethasone dipropionate (84 μg/spray) aqueous nasal spray in the treatment of seasonal allergic rhinitis

Abstract BACKGROUND: The use of intranasally administered corticosteroid sprays is an established treatment option for seasonal allergic rhinitis. METHODS: In this double-blind, placebo-controlled, multicenter study, 438 patients with moderate to severe symptoms of seasonal allergic rhinitis were treated for 4 weeks with double-strength beclomethasone dipropionate (BDP) aqueous nasal spray (84 μg/spray: BDP-ds), once daily; regular-strength BDP (42 μg/spray: BDP-rs), twice daily; high-strength BDP (336 μg/spray: BDP-hs), once daily; or placebo. BDP-hs was included as a safety comparison group. All treatments were given as two sprays per nostril. RESULTS: Physician-rated nasal symptom scores were significantly improved in all three active treatment groups compared with those of the placebo group within the initial 3 days of treatment. Improvement was maintained throughout the 4-week treatment period. BDP-ds and BDP-rs were equivalent at all time points. The BDP-ds, BDP-rs, and BDP-hs groups had greater numbers of patients with a good or excellent therapeutic response at end point than the placebo group. All treatments were well-tolerated, and no unexpected adverse events were reported. No effects on laboratory evaluations or vital signs were evident for any treatment group. CONCLUSIONS: The results of this study show that BDP-ds given once a day and BDP-rs given twice a day in the same total daily dose are comparably safe and effective in the treatment of patients with seasonal allergic rhinitis. (J ALLERGY CLIN IMMUNOL 1996;98:302-8.)

Efficacy and safety of azelastine nasal spray at a dose of 1 spray per nostril twice daily

BACKGROUNDnAzelastine hydrochloride nasal spray is available worldwide for the treatment of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis. One spray per nostril twice daily is the most commonly recommended dose.nnnOBJECTIVEnTo determine the efficacy and safety of azelastine nasal spray, 1 spray per nostril twice daily, in patients with SAR.nnnMETHODSnIn 2 studies conducted in the United States we assessed 554 patients with moderate-to-severe SAR who were still symptomatic after a 1-week placebo lead-in period. Patients were randomized to 2 weeks of double-blind treatment with azelastine nasal spray, 1 spray per nostril twice daily, or placebo nasal spray. The primary efficacy variable was change from baseline in total nasal symptom score, consisting of sneezing, itchy nose, runny nose, and nasal congestion.nnnRESULTSnMean differences in total nasal symptom score between the azelastine and placebo groups were significant in both studies: 2.69 vs 1.31 (P = .01) in study 1 and 3.68 vs 2.50 (P = .02) in study 2. Bitter taste was reported by 8.3% of patients treated with 1 spray per nostril twice daily compared with the labeled incidence of 19.7% with 2 sprays per nostril twice daily. Somnolence was reported by 1 patient (0.4%) using the 1-spray regimen compared with the labeled incidence of 11.5% using the 2-spray regimen.nnnCONCLUSIONSnAzelastine nasal spray at a dose of 1 spray per nostril twice daily is effective and has improved tolerability compared with 2 sprays per nostril twice daily in patients with SAR.

Brompheniramine, Loratadine, and Placebo in Allergic Rhinitis: A Placebo-Controlled Comparative Clinical Trial

A double‐blind, randomized, placebo‐controlled, parallel‐group, multicenter study was conducted to compare the effectiveness of an extended‐release formulation of a classical antihistamine, brompheniramine, and a second‐generation compound, loratadine, in the treatment of allergic rhinitis. Subjects with symptoms of allergic rhinitis received brompheniramine 12 mg twice daily (n = 112), loratadine 10 mg once daily (n = 112), or placebo twice daily (n = 114) for 7 days. Study medications were blinded using a double‐dummy technique. Subjects completed an overall evaluation of symptom relief on a daily basis and returned on treatment days 3 and 7, at which times the investigator assessed symptom severity. The investigator and subject each completed a global efficacy evaluation, and subjects were interviewed regarding adverse experiences. The primary efficacy variable was the physicians global efficacy evaluation on day 3. Symptoms also were analyzed as summed severity scores for all symptoms and for the nasal symptom cluster of rhinorrhea, sneezing, and nasal blockage. At all post‐baseline evaluations (days 3, 7, and averaged over the two days), brompheniramine was significantly better than loratadine and placebo for both sets of summed symptom scores and all three global assessments. Loratadine was significantly better than placebo for physician ratings of total symptom severity averaged over the two days and for the physician and subject ratings of the nasal cluster on day 3. Central nervous system‐related symptoms were the most frequently reported adverse experiences; somnolence was reported most frequently by patients taking brompheniramine, and its occurrence was less frequent as treatment continued. A nonprescription, extended‐release formulation of brompheniramine 12 mg twice daily provided significantly better relief of symptomatic allergic rhinitis than loratadine 10 mg once daily.

Adult and paediatric poor metabolisers of desloratadine: an assessment of pharmacokinetics and safety

Antihistamines are widely used to treat allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) in adults and children. Desloratadine is a once-daily oral antihistamine with a favourable sedation profile that is approved for the treatment of AR and CIU. Phenotypic polymorphism in the metabolism of desloratadine has been observed, such that some individuals have a decreased ability to form 3-hydroxydesloratadine, the major metabolite of desloratadine; such individuals are termed ‘poor metabolisers of desloratadine’. This review describes the prevalence of poor metabolisers of desloratadine, quantifies the exposure to desloratadine in poor metabolisers and demonstrates that the increased exposure in poor metabolisers is independent of age when administered at age-appropriate doses. Furthermore, this review demonstrates that the increased exposure to desloratadine in poor metabolisers is not associated with any changes in the safety and tolerability profile of desloratadine, including cardiovascular safety.

Asthma 2008: Targeting Immunoglobulin E to Achieve Disease Control

Traditionally, practice guidelines have recommended a step-wise approach to treatment based on asthma severity and lung function. However, increasing evidence suggests that asthma may not be adequately controlled in many patients with moderate-to-severe disease despite aggressive therapy, and that regularly evaluating the level of asthma control achieved in individual patients may be more effective than disease severity in guiding treatment decisions. This is reflected in updated asthma guidelines from the National Asthma Education and Prevention Program, which advocate regular assessment of asthma control in terms of the current impairment and future risk associated with the disease. Guideline-recommended options for patients with persistent, moderate-to-severe immunoglobulin E (IgE)–mediated asthma have recently been enhanced by the inclusion of omalizumab. This change is based on growing evidence for the central role of IgE in airway inflammation and asthma and the clinical effectiveness of blocking IgE with omalizumab, a recombinant humanized monoclonal antibody. Omalizumab significantly reduced asthma exacerbations and improved lung function and symptoms in randomized controlled studies of patients inadequately controlled on inhaled corticosteroids plus long-acting β2-agonist therapy; these benefits for reducing asthma impairment and risk were maintained during steroid dose reductions. Omalizumab is well tolerated, although patients should be monitored for possible rare anaphylactic reactions.

Double-blind, placebo-controlled trial of reformulated azelastine nasal spray in patients with seasonal allergic rhinitis

Background Azelastine nasal spray is a topical antihistamine with a distinctive taste that may be objectionable to some patients. The primary objectives of this clinical trial were (1) to determine if a reformulated azelastine nasal spray (Astepro) with sucralose as a taste-masking agent provides comparable efficacy to the original formulation (Astelin) and (2) to evaluate dose–response relationships between groups. Methods Eight hundred thirty-five patients with seasonal allergic rhinitis were randomized to six treatment groups: (1) original azelastine nasal spray, 1 spray/nostril b.i.d.; (2) reformulated azelastine, 1 spray/nostril b.i.d.; (3) placebo, 1 spray/nostril b.i.d.; (4) original azelastine nasal spray, 2 sprays/nostril b.i.d., (5) reformulated, 2 sprays/nostril b.i.d.; and (6) placebo, 2 sprays/nostril b.i.d. The primary efficacy variable was the change from baseline to day 14 in total nasal symptom score (TNSS) consisting of runny nose, sneezing, itchy nose, and nasal congestion. Results Original azelastine nasal spray and the reformulated spray produced comparable improvements in the TNSS at both dosages. There was a dose-related difference in TNSS comparing the 1- and 2-spray dosages. The percentage changes from baseline in the TNSS in the 2-sprays/nostril dosage groups were 27.9% (p < 0.001) with the reformulated nasal spray, 23.5% (p < 0.01) with the original formulation, and 15.4% with placebo. The incidence of bitter taste was 7% with the reformulated spray and 8% with the original at the 2-sprays/nostril dosage. Conclusion The results of this study showed efficacy both with original azelastine nasal spray and with the reformulated nasal spray and a clear dose–response difference between the 1- and 2-spray dosages.

A One-Week Dose-Ranging Study of Inhaled Salmeterol in Children with Asthma

This was a 1-week study evaluating the safety and efficacy of two dosage regimens of salmeterol in children with asthma. A total of 243 children, aged 4-11 years, with mild-to-moderate asthma were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating salmeterol xinafoate 21 micrograms and 42 micrograms administered via metered-dose inhaler (MDI) twice daily for 1 week. Patients were allowed to use albuterol MDI as needed for relief of acute symptoms. Inhaled corticosteroids and/or cromolyn at fixed dosages could be continued during the study, but theophylline and oral beta-agonists were not allowed. Twelve-hour serial spirometry (for patients aged 6-11 years) and serial peak expiratory flow rate (PEFR) (all patients) were performed on days 1 and 8 of treatment; morning and evening PEFR were recorded each day prior to inhalation of the study drug. Safety was assessed by monitoring adverse events, clinical laboratory values, vital signs, electrocardiogram (ECG), and 24-hr ECG (Holter) monitoring. Both the 21-micrograms and 42-micrograms doses of salmeterol produced significantly greater bronchodilation, as measured by 12-hr serial forced expiratory volume in 1 sec (FEV1) (p < or = 0.02) and PEFR (p < or = 0.001), than did placebo on days 1 and 8. A small dose-response was observed, with the 42-micrograms dosage producing consistently higher serial FEV1 and PEFR than did the 21-micrograms dosage, although the differences were not statistically significant. Morning and evening PEFR increased significantly (p < or = 0.008) with both dosages of salmeterol compared with placebo. Twelve patients (5%) experienced potentially drug-related adverse events, with headache (4% in each salmeterol group) being the most common. There were no clinically significant changes in heart rate as measured by Holter monitoring, ECGs, vital signs, or clinical laboratory values following treatment with either dose of salmeterol. Salmeterol 21 micrograms or 42 micrograms twice daily was effective in producing bronchodilation in children aged 4-11 years, and both dosages had good safety profiles. Patients treated with salmeterol 42 micrograms twice daily showed a trend toward greater improvement in asthma control compared with those who received salmeterol 21 micrograms.

Combination Therapy: Appropriate for Everyone?

The severity of asthma often varies throughout the course of the disease. At times the symptoms and underlying inflammation that are characteristic of asthma can worsen. Thus during an episode of viral-induced asthma or during a seasonal increase in asthma severity, a patient may be directed to increase his or her dosage of asthma controllers (i.e., inhaled corticosteroid) or add a long-acting bronchodilator (or other controller medications such as antileukotrienes) to manage symptoms, as recommended in guidelines published by the National Institutes of Health (NIH). Similarly, when symptoms are stable, decreasing dosages or discontinuing certain medications may be appropriate. The recent introduction of a combination product, of a long-acting bronchodilator formulated in the same dry powder device with an inhaled corticosteroid raises new challenges for the step care approach to asthma management recommended by the NIH in 1997. Although unquestionably more convenient for the patient, a combination formulation has the potential to decrease the flexibility required to successfully manage asthma over long periods. In addition, controversy exists regarding long-acting beta-agonists alone because their regular use may mask inflammation in the lung and decrease responsiveness to the bronchodilating effects of rescue medications (i.e., short-acting beta-agonists). The purpose of this article is to help physicians make informed therapeutic decisions for their patients with asthma. It focuses on the advantages and potential disadvantages of using combination products, which contain both an inhaled corticosteroid and a long-acting beta-agonist in the context of the NIH step care approach. Recent publications outlining the use of other add-on controller medications are also discussed.