d-Amphetamine Transdermal System in Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Secondary Endpoint Results and Post Hoc Effect Size Analyses from a Pivotal Trial.

Objectives: Amphetamines are a preferred treatment for attention-deficit/hyperactivity disorder (ADHD), with the dextroamphetamine transdermal system (d-ATS) providing an alternative to oral formulations. A pivotal trial of d-ATS in children and adolescents with ADHD met primary and key secondary endpoints. This analysis reports additional endpoints and safety findings from the pivotal trial and evaluates effect size and number needed to treat (NNT) for d-ATS. Methods: In this study, a 5-week, open-label dose-optimization period (DOP) preceded a 2-week, randomized, crossover double-blind treatment period (DBP). Eligible patients received d-ATS 5 mg during the DOP, with weekly evaluations for increase to 10, 15, and 20 mg (equivalent to labeled doses of 4.5, 9, 13.5, and 18 mg/9 hours, respectively) until reaching and maintaining the optimal dose, which was utilized for the DBP. Secondary endpoints included assessment of Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV), Conners' Parent Rating Scale Revised Short Form (CPRS-R:S), and Clinical Global Impression (CGI) scores. NNT was calculated for ADHD-RS-IV and CGI-Improvement (CGI-I). Safety assessments included treatment-emergent adverse events (TEAEs) and dermal safety. Results: In total, 110 patients entered the DOP, with 106 patients randomized (DBP). During the DBP, the least-squares mean (95% confidence interval) difference for d-ATS versus placebo in ADHD-RS-IV total score was -13.1 (-16.2 to -10.0; p < 0.001), with effect size of 1.1 and NNT of 3 for ADHD-RS-IV remission, ≥30% improvement, and ≥50% improvement. Significant differences between placebo and d-ATS were also observed for CPRS-R:S and CGI-I scales (p < 0.001), with NNT of 2 for CGI-I response. Most TEAEs were mild or moderate, with three leading to study discontinuation in the DOP and none in the DBP. No patients discontinued due to dermal reactions. Conclusions: d-ATS was effective in treating ADHD in children and adolescents, meeting all secondary endpoints, with a large effect size and NNT of 2-3 to achieve a clinically meaningful response. d-ATS was safe and well tolerated, with minimal dermal reactions. Clinical Trial Registration: NCT01711021.

Objective and self-reported evidence of dextromethorphan antitussive efficacy in children, aged 6-11 years, with acute cough due to the common cold.

OBJECTIVE: To determine objective and subjective endpoints most suitable for evaluating antitussive efficacy of dextromethorphan hydrobromide (DXM) in children. Spontaneous resolution of acute cough and large placebo effects are impediments to evaluating antitussive efficacy. Another impediment is paucity of age-appropriate, validated cough assessment tools. METHODS: This was a multiple-dose, double-blind, placebo-controlled, randomized, pilot clinical study in children, aged 6-11 years, with cough due to the common cold. Eligible subjects met entry criteria and qualified by completing a run-in period where coughs were recorded with a cough monitor after they were dosed with sweet syrup. They were subsequently randomized to receive DXM or placebo over 4 days. Coughs were recorded during the initial 24 h; subjective assessments of cough severity and frequency were self-reported daily during treatment. RESULTS: Data from 128 evaluable subjects (67 DXM; 61 placebo) were analyzed. Total coughs over 24-hours (primary endpoint) and cough frequency during daytime were reduced by 21.0% and 25.5%, respectively, with DXM relative to placebo. Also, greater reductions in cough severity and frequency were self-reported with DXM. These findings were statistically significant and medically relevant. No effects were detected between treatments for nighttime cough rates or impact of cough on sleep. Multiple doses of DXM and placebo were generally well-tolerated. CONCLUSION: Evidence of DXM antitussive efficacy was shown in children using objective and subjective assessment tools validated in pediatric populations. Diurnal variation of cough frequency over 24 h reduced the assay sensitivity needed to detect treatment differences at nighttime, as coughs/hour decreased during sleep for both groups.

Efficacy and Safety of Dextroamphetamine Transdermal System for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results from a Pivotal Phase 2 Study.

Objectives: To assess efficacy and safety of the new Dextroamphetamine Transdermal System (d-ATS) to treat children and adolescents (aged 6-17 years) with attention-deficit/hyperactivity disorder (ADHD). Methods: In this phase 2, randomized, placebo-controlled study, 4 d-ATS patches of differing doses (5, 10, 15, and 20 mg) were evaluated. Patients began a 5-week, open-label, stepwise dose-optimization period in which they received a 5-mg d-ATS patch (applied to hip) for 9 hours. During weekly visits, patients were evaluated for possible adjustments to the next dose level based on efficacy and safety. Once at the optimal dose, that dose was maintained during a 2-week, crossover double-blind treatment period. Primary endpoint was to assess efficacy of d-ATS versus placebo as measured by Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP) total score; key secondary endpoints included assessing onset and duration of efficacy by SKAMP total score, and additional secondary endpoints included Permanent Product Measure of Performance (PERMP) scores. Safety was assessed throughout. Results: d-ATS treatment resulted in significant improvements versus placebo in ADHD symptoms as measured by SKAMP total score, with overall least-squares mean difference (95% confidence interval) versus placebo of -5.87 (6.76, -4.97; p < 0.001) over the 12-hour assessment period. Onset of efficacy was observed at 2 hours postdose (p < 0.001), and duration of effect continued through 12 hours (patch removed at 9 hours), with significant differences between d-ATS and placebo at all time points from 2 hours onward (all p ≤ 0.003). Significant improvements versus placebo in PERMP-A and PERMP-C scores were also observed from 2 to 12 hours postdose with d-ATS treatment. d-ATS was safe and well-tolerated, with a systemic safety profile similar to that observed with oral amphetamines. Conclusions: This study demonstrates that d-ATS is an effective and well-tolerated treatment for children and adolescents with ADHD. These data indicate that d-ATS can deliver sustained levels of efficacy along with the advantages of transdermal drug delivery, making it a beneficial new treatment option. Clinical Trial Registration no.: NCT01711021.

Safety and tolerability of fixed-dose combinations of ibuprofen and acetaminophen: pooled analysis of phase 1-3 clinical trials.

OBJECTIVES: An ibuprofen (IBU)/acetaminophen (APAP) fixed-dose combination (FDC) for over-the-counter (OTC) use was developed with the goal of providing the same effective analgesic activity as full doses of the individual monocomponents, while reducing individual monocomponent drug exposures. Here, the safety and tolerability of the FDC is characterized using pooled safety data from phase 1-3 clinical trials in the FDC development program. METHODS: We conducted a pooled safety analysis of data from 7 clinical trials: three phase 1 pharmacokinetic trials, a phase 2 proof-of-concept trial, and three phase 3 trials (a single- and a multiple-dose trial in a dental pain model and a single-dose trial in an induced-fever model). Safety and tolerability of the FDC were assessed by adverse events (AEs) for the total group and subgroups (age, sex, race). RESULTS: A total of 1,477 participants were enrolled in the 7 trials; 715 were treated with FDC IBU/APAP, 432 with IBU monotherapy, 330 with APAP monotherapy, and 156 with placebo. Most subjects were white (86.5%), and 44% were female. Two trials enrolling 195 adolescents accounted for 13.2% of the overall study population. All-causality treatment-emergent AEs (TEAEs) occurred in 19.7% of the 1477 participants. Nausea (13.5%), vomiting (7.4%), dizziness (4.5%), headache (1.2%), and feeling hot (1.0%) were the only TEAEs reported in ≥1% of subjects. Treatment-related AEs occurred in 1.8% of the subjects in the overall population. The incidence of AEs, including treatment-related AEs, was consistently lower in all active treatment groups than in the placebo group; this also applied to subgroups according to sex, race, and age, including adolescents aged 12-17 years. The higher rate of AEs with placebo was likely due to lack of pain/fever control. CONCLUSION: Single-dose or short-course FDC IBU/APAP OTC use was well tolerated, with an AE profile similar to its IBU and APAP monocomponents. CLINICALTRIALS.GOV REGISTRATION: NCT01559259; NCT02912650; NCT02837952; NCT02761980. The pharmacokinetic studies (n = 3) did not require registration.

Phase I Pharmacokinetic Study of Fixed-Dose Combinations of Ibuprofen and Acetaminophen in Healthy Adult and Adolescent Populations.

INTRODUCTION: A fixed-dose combination (FDC) of ibuprofen and acetaminophen has been developed that provides greater analgesic efficacy than either agent alone at the same doses without increasing the risk for adverse events. METHODS: We report three clinical phase I studies designed to assess the pharmacokinetics (PK) of the FDC of ibuprofen/acetaminophen 250/500 mg (administered as two tablets of ibuprofen 125 mg/acetaminophen 250 mg) in comparison with its individual components administered alone or together, and to determine the effect of food on the PK of the FDC. Two studies in healthy adults aged 18-55 years used a crossover design in which subjects received a single dose of each treatment with a 2-day washout period between each. In the third study, the bioavailability of ibuprofen and acetaminophen from a single oral dose of the FDC was assessed in healthy adolescents aged 12-17 years, inclusive. RESULTS: A total of 35 and 46 subjects were enrolled in the two adult studies, respectively, and 21 were enrolled in the adolescent study. Ibuprofen and acetaminophen in the FDC were bioequivalent to the monocomponents administered alone or together. With food, the maximum concentration (Cmax) for ibuprofen and acetaminophen from the FDC was reduced by 36% and 37%, respectively, and time to Cmax (i.e. tmax) was delayed. Overall drug exposure to ibuprofen or acetaminophen in the fed versus fasted states was similar. In adolescents, overall exposure to acetaminophen and ibuprofen was comparable with that in adults, with a slightly higher overall exposure to ibuprofen. Exposure to acetaminophen and ibuprofen in adolescents aged 12-14 years was slightly higher versus those aged 15-17 years. Adverse events were similar across all treatment groups. CONCLUSIONS: The FDC of ibuprofen/acetaminophen 250/500 mg has a PK profile similar to its monocomponent constituents when administered separately or coadministered, indicating no drug-drug interactions and no formulation effects. Similar to previous findings for the individual components, the rates of absorption of ibuprofen and acetaminophen from the FDC were slightly delayed in the presence of food. Overall, adolescents had similar exposures to acetaminophen and ibuprofen as adults, while younger adolescents had slightly greater exposure than older adolescents, probably due to their smaller body size. The FDC was generally well tolerated.

Brompheniramine and Chlorpheniramine Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

Two pediatric studies characterized brompheniramine and chlorpheniramine pharmacokinetics in a total of 72 subjects, aged 2 to 17 years. A single age-/weight-based oral dose, ranging from 1 to 4 mg, was administered with 2 to 6 oz of water at least 2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed using high-pressure liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods; relationships with age were assessed using linear regression. Results indicated that for brompheniramine and chlorpheniramine, Cmax was similar across age groups, although it tended to occur earlier in the youngest group. AUC was ∼15% to 30% higher in the oldest age group. As expected, CLo and Vz /F increased with age; however, following allometric scaling, no age-related differences existed. Because the increase with age for both parameters was similar, no age-related differences in t1/2,z existed (∼15 hours). Overall, the single doses were well tolerated. Sedation was the most common reported AE and appeared to be more prevalent in the 2- to 5-year-old group. Overall, these results indicate that an age/weight dosing nomogram using a 4-fold range of doses achieves similar Cmax and AUC.

Actual use of and adherence to ibuprofen 400 mg tablet dosing instructions in a simulated OTC environment
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OBJECTIVE: Evaluate adherence of US consumers to proposed label directions for a new 400 mg ibuprofen formulation. METHODS: In this single-arm, open-label, multicenter, 30-day study simulating an over-the-counter (OTC)-like environment, US analgesic consumers reviewed proposed product packaging for a new 400 mg ibuprofen formulation and made a purchase decision. Purchasers used the product as needed and recorded use over 30 days. Outcomes included the percentage of participants who exhibited correct or acceptable product use for the primary endpoint (not exceeding 1,200 mg/day > 2 times during the study) or secondary endpoint (not exceeding 400 mg/dose > 2 times during the study) and adherence to the labeled dosing interval of 6 - 8 hours. Primary endpoint success was met if the lower bound of the 95% confidence interval (CI) was ≥ 85%. RESULTS: Of 685 purchasers providing use data, correct or acceptable use behavior occurred in 95.2% (95% CI: 93.6%, 96.8%) regarding total daily dose and in 84.4% (95% CI: 81.7%, 87.1%) regarding the number of tablets taken per dosing occasion. Most participants (87.3%) never used > 1,200 mg/day or took > 1 tablet/dose (78.1%). Nearly 43% of subjects re-dosed within 6 hours of the previous dose; of these, ~ 82% re-dosed between the 4- and 6-hour time intervals. Adverse events were consistent with prior ibuprofen 200 mg experience. CONCLUSION: This study provides evidence that a majority of US consumers would be able to use OTC ibuprofen 400 mg tablets in a manner consistent with product labeling. Misuse rates were low and unlikely to generate an excess risk of clinically important adverse events.
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Analgesic Efficacy of a New Immediate-Release/Extended-Release Formulation of Ibuprofen: Results From Single- and Multiple-Dose Postsurgical Dental Pain Studies.

Analgesic effects of ibuprofen immediate-release/extended-release (IR/ER) 600-mg tablets were evaluated in 2 randomized, double-blind, placebo-controlled dental pain studies. Patients 16-40 years old with moderate-severe pain following third-molar extraction received single-dose ibuprofen 600 mg IR/ER (formulation A or B), naproxen sodium 220 mg, or placebo (2:2:2:1; study 1) or 4 doses of ibuprofen 600 mg IR/ER (formulation A) or placebo (1:1; study 2). In study 1 (n = 196), mean (standard deviation [SD]) time-weighted sum of pain intensity difference scores for placebo, ibuprofen IR/ER A, ibuprofen IR/ER B, and naproxen, respectively, were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) over 0-12 hours and -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) over 8-12 hours (all P < .001 vs placebo). In study 2 (n = 106), mean (SD) time-weighted sum of pain relief and pain intensity difference scores were 18.2 (20.0) versus 41.5 (21.0) at 0-12 hours and 10.3 (12.0) versus 18.4 (12.1) at 8-12 hours for placebo versus ibuprofen IR/ER, respectively (P < .001 for both); efficacy was sustained over each of the four 12-hour dosing intervals with ibuprofen. Gastrointestinal adverse events predominated with placebo both after study medication administration and after rescue medication use, if applicable. Ibuprofen 600 mg IR/ER provided safe and effective analgesia after single and multiple doses.

Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate.

BACKGROUND: Anabolic responsiveness to teriparatide can be blunted or delayed in patients previously treated with alendronate. The extent of this effect is different for other antiresorptives. This study evaluated the early anabolic effects of teriparatide in postmenopausal women with osteoporosis previously treated with alendronate or risedronate. METHODS: Patients treated for at least 24 months with alendronate or risedronate discontinued their bisphosphonate and received teriparatide for 12 months. The primary endpoint was a comparison of changes from baseline in N-terminal propeptide of type 1 collagen after 3 months between prior bisphosphonate groups. We also examined changes in other bone turnover markers, bone mineral density (BMD), and relationships between early changes in bone turnover markers and 12-month areal and volumetric BMD. RESULTS: In the prior risedronate group, the N-terminal propeptide of type 1 collagen increase was significantly greater after 3 months of teriparatide than in the prior alendronate group (mean +/- se, 86.0 +/- 5.6 vs. 61.2 +/- 5.3 ng/ml, respectively; P < 0.001). Findings were similar for the other bone turnover markers. The changes in areal BMD and trabecular spine volumetric BMD were also greater in the prior risedronate group (P < 0.05). Early changes in bone turnover markers correlated with changes in trabecular spine volumetric BMD at 12 months (Spearman r = 0.45). Teriparatide was well tolerated. CONCLUSION: This nonrandomized but prospective study suggests that there may be differences in anabolic responsiveness to teriparatide as a function of the type of prior bisphosphonate exposure.

The effect of fexofenadine hydrochloride on productivity and quality of life in patients with chronic idiopathic urticaria.

The present study examined the impact of once-daily fexofenadine hydrochloride (HCl) 180 mg on health-related quality of life (HRQL) in subjects with chronic idiopathic urticaria (CIU). This was a multicenter, randomized, double-blind. parallel-group, placebo-controlled study. Subjects completed the Dermatology Life Quality Index (DLQI) and the Work Productivity and Activity Impairment (WPAI) questionnaire at baseline and at weeks 2 and 4. The primary HRQL end point was mean change from baseline to week 4 in total DLQI score. Subjects in the fexofenadine HCl treatment group (n = 163) experienced significantly greater improvements in mean total DLQI score (P = .0219) and in the individual domains of symptoms and feelings (P = .0119) and personal relationships (P = .0091) compared with those in the placebo group (n = 91). Subjects who received fexofenadine HCl experienced less work productivity impairment, overall work impairment, and activity impairment than those who received placebo. The results indicated that once-daily fexofenadine HCl 180 mg improved the HRQL of subjects with CIU, as assessed by change in total DLQI score.

Onset of action of fexofenadine hydrochloride 60 mg/pseudoephedrine hydrochloride 120 mg in subjects aged 12 years with moderate to severe seasonal allergic rhinitis: a pooled analysis of two single-dose, randomized, double-blind, placebo-controlled allergen exposure unit studies.

BACKGROUND: The onset of action of antihistamine-decongestant combinations is an important factor in the treatment of subjects with seasonal allergic rhinitis (SAR). OBJECTIVE: This was a pooled analysis of 2 published studies with identical designs investigating the onset of action of the combination of fexofenadine hydrochloride 60 mg/pseudoephedrine hydrochloride 120 mg (FEX60/PSE120) in subjects with moderate to severe SAR. METHODS: Subjects aged 12 years received single doses of FEX60/PSE120 or placebo in 2 randomized, double-blind, placebo-controlled, parallel-group, allergen exposure unit studies and recorded their SAR symptoms on diary cards before dosing, at 15-minute intervals for 2 hours after dosing, and at 30-minute intervals for the next 4 hours. The primary efficacy end point was onset of action, assessed in terms of absolute change in the major symptom complex (MSC) score, which was the sum of scores for the individual symptoms of stuffy nose, itchy nose, runny nose, watery eyes, itchy eyes, itchy ears/throat, and sneezing. Secondary end points included the absolute and percent change in the total symptom complex (TSC) score (the sum of the MSC score plus the scores for nose blowing, sniffles, postnasal drip, and cough) and individual symptom scores. Treatment-emergent adverse events (TEAEs) were recorded. Analyses were performed on the modified intention-to-treat (mITT) population, which included all subjects who were randomized to treatment and took the single dose of study medication according to the protocol. RESULTS: A total of 1693 subjects were screened in the 2 studies, and 786 were randomized (298 in study 1, 488 in study 2). Two subjects withdrew from study 2; therefore, the mITT population consisted of 784 subjects. Subjects' mean age was 33.4 years, and 64.4% were female. The onset of action of FEX60/PSE120 was 45 minutes; the least squares mean (SD) treatment difference in the change from baseline in absolute MSC score was 0.8 (0.31) (95% CI, 0.2-1.4; P = 0.008). All subsequent changes from baseline in MSC scores were statistically significant for FEX60/PSE120 compared with placebo (P < 0.001). The absolute and percent change in TSC score and the percent change in MSC score were significantly decreased at all time points from 45 minutes after dosing for FEX60/PSE120 compared with placebo (all, P < 0.05). Individual symptoms (mean of hours 1 to 5) also were significantly improved with FEX60/PSE120 compared with placebo (all, P < 0.05). TEAEs were reported by 2.3% (9/391) and 4.3% (17/393) of subjects receiving FEX60/PSE120 and placebo, respectively. The most commonly occurring TEAS in the FEX60/PSE120 and placebo groups was somnolence (n = 4 and n = 6, respectively). CONCLUSION: In this pooled analysis of 2 allergen exposure unit studies, FEX60/PSE120 had an onset of action of 45 minutes and a sustained effect throughout the 6-hour study period in subjects with moderate to severe SAR.

Efficacy of fexofenadine in the prophylactic control of cat allergen-induced allergic rhinitis.

BACKGROUND: To date, it is unknown whether fexofenadine mitigates the worsening of symptoms induced by the cat allergen Felis domesticus allergen 1. OBJECTIVE: To determine the effects of a single dose of fexofenadine hydrochloride, 180 mg, in preventing and controlling cat allergen-induced allergic rhinitis symptoms using the cat room challenge model. METHODS: This single-center, randomized, double-blind, placebo-controlled, 2-way crossover study consisted of a screening visit, 1 or 2 qualifying visits, and 2 treatment periods separated by a mean +/- SD washout period of 14 +/- 3 days. Patients were randomized to treatment sequence 1 (placebo followed by fexofenadine) or sequence 2 (fexofenadine followed by placebo). Baseline end points were obtained before study drug administration, and allergen challenges were initiated 1 1/2 hours after dosing. The primary end point was the change from predose baseline in the total symptom score (sum of rhinorrhea, itchy nose/palate/ throat, sneezing, and itchy/watery/red eyes) after 30 minutes of allergen exposure compared with placebo. RESULTS: Of 211 patients screened, 66 were randomized and 63 completed the study. Mean change in the total symptom score from predose baseline was significantly less with fexofenadine compared with placebo 30 minutes after initiation of the cat allergen challenge (2 hours after dosing) (P = .03). The overall incidence of treatment-emergent adverse events was low and comparable for both groups. CONCLUSION: Prophylactic treatment with a single dose of fexofenadine hydrochloride, 180 mg, significantly mitigated the worsening of allergic rhinitis symptoms induced by exposure to cat allergen compared with placebo use.

Comparative effects of fexofenadine and montelukast on allergen-induced wheal and flare.

Comparisons of the efficacy, onset and duration of action of fexofenadine and montelukast are limited. This study evaluated the pharmacodynamic properties of these agents in an allergen-induced wheal-and-flare model. This randomized, placebo-controlled, crossover study was composed of three treatment periods and two visits on consecutive days for each period, with each period separated by a 14-day (+/-4) washout. At each treatment visit, subjects received a predose allergen skin-prick test followed by either a single dose of fexofenadine HCl 180 mg, montelukast sodium 10 mg, or placebo. Allergen skin-prick testing was performed at 20, 40, and 60 minutes, then hourly through 12 hours and at 23 hours and 24 hours postdose. Adults (n = 48) with positive skin-prick tests were included in the analysis. Significant flare inhibition occurred from 40 minutes through 24 hours postdose for fexofenadine versus placebo (p < 0.05), whereas montelukast did not reach statistical significance for flare inhibition at any time point compared with placebo. Significant wheal inhibition occurred from 60 minutes through 24 hours postdose for fexofenadine versus placebo (p = 0.0012); montelukast did not significantly suppress wheal versus placebo at any time point. Fexofenadine had greater suppression than montelukast for both wheal and flare from 40 minutes through 24 hours (p < .05). Maximum suppression of flare and wheal reached 79.0 and 72.3% for fexofenadine, and 7.3 and 9.6% for montelukast. Fexofenadine suppressed the allergen-induced wheal-and-flare response to a significantly greater extent, and had a significantly faster onset of action, compared with montelukast.

Once-daily fexofenadine treatment for chronic idiopathic urticaria: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Chronic idiopathic urticaria (CIU) can have a profound effect on patients' health and quality of life. OBJECTIVE: To evaluate the efficacy and safety of once-daily dosing of fexofenadine hydrochloride, 180 mg, on CIU. METHODS: This randomized, double-blind, parallel-group, placebo-controlled study consisted of a placebo run-in period followed by a 4-week treatment period. Patients 12 years and older with active CIU were randomized 2:1 to receive once-daily fexofenadine, 180 mg, or placebo. The primary end points were change from baseline in mean daily number of wheals (MNW score) and mean daily severity of pruritus during treatment. Secondary efficacy measures included modified total symptom scores and MNW and pruritus severity scores evaluated weekly and instantaneously at trough drug levels. RESULTS: Patients administered fexofenadine (n = 163) experienced significantly greater improvements in MNW and pruritus severity scores compared with the placebo group (n = 92) (P < .001 for both). Similarly, throughout treatment and at each individual week, the mean reductions in modified total symptom scores were significantly greater in the fexofenadine group (P < or = .005 for all comparisons vs placebo). The mean reductions in instantaneous MNW and pruritus severity scores were greater in patients in the fexofenadine group than in those who received placebo (MNW score: P = .015; pruritus severity score: P < .001). There were no significant differences in the frequency of treatment-emergent adverse events between the 2 treatment groups. CONCLUSIONS: A once-daily dose of fexofenadine hydrochloride, 180 mg, offered effective, well-tolerated relief for the management of CIU.

Fexofenadine HCl 60 mg/ pseudoephedrine HCl 120 mg has a 60-minute onset of action in the treatment of seasonal allergic rhinitis symptoms, as assessed in an allergen exposure unit.

Although antihistamine-decongestant combinations are frequently used for allergic rhinitis, published data about the onset of action of these combination agents are limited. This randomized, double-blind, placebo-controlled, parallel-group study investigated the onset of action, efficacy, and safety of fexofenadine HCl 60 mg/pseudoephedrine HCl 120 mg or placebo in patients with moderate-to-severe seasonal allergic rhinitis in an allergen exposure unit. Assessments included major symptom complex (MSC) score (sum of sneezing, itchy nose, runny nose, watery eyes, itchy eyes, itchy ears/throat, and stuffy nose), and total symptom complex (TSC) score (MSC symptoms plus nose blows, sniffles, postnasal drip, and cough). Onset of action was defined as the first time that two consecutive, statistically significant absolute changes in MSC scores from baseline were achieved for study drug relative to placebo. The onset of action for the combination was 60 minutes (mean absolute MSC change from baseline: -6.9 +/- 0.3 for the combination compared with -5.9 +/- 0.3 for placebo from a baseline of 17.0 and 16.8, respectively; p < 0.05) for the modified intention-to-treat population (n = 486). Reductions in absolute MSC scores were significantly greater with the combination than placebo at all subsequent time points (p < 0.01). The combination resulted in significantly greater reductions compared with placebo for percent MSC, absolute TSC, and percent TSC scores at 60 minutes postdose (all p < 0.05) and throughout the study (all p < 0.05). The incidence of adverse events was 1.6 and 3.3% for the combination and placebo, respectively. In conclusion, fexofenadine HCl 60 mg/pseudoephedrine HCl 120 mg is effective in the treatment of patients with moderate-to-severe seasonal AR, with an onset of action of 60 minutes and a good safety profile.

Anti-inflammatory activity of H1-receptor antagonists: review of recent experimental research.

OBJECTIVE: To compare the anti-inflammatory effects of fexofenadine with other H(1)-receptor antagonists in vitro. DATA SOURCES: Published literature. STUDY SELECTION: Recent experimental studies on anti-inflammatory effects of H(1)-receptor antagonists. Databases searched: Medline, Medscape. PERIOD COVERED: 1990-2003. Search terms: second-, third-generation antihistamines; sedating, nonsedating antihistamines; in vitro anti-inflammatory activity; cetirizine; ebastine; loratadine; fexofenadine; desloratadine. RESULTS: Second- and third-generation H(1)-receptor antagonists may demonstrate significant in vitro anti-inflammatory activity at concentrations considered to be clinically relevant. In some instances, higher (supraclinical) concentrations are required to achieve comparable effects. CONCLUSIONS: Experimental research suggests that second- and third-generation H(1)-receptor antagonists may achieve anti-inflammatory effects in a clinical context. Further studies are required to support this conclusion.

Fexofenadine hydrochloride, 180 mg, exhibits equivalent efficacy to cetirizine, 10 mg, with less drowsiness in patients with moderate-to-severe seasonal allergic rhinitis.

BACKGROUND: Previous studies have shown that fexofenadine and cetirizine effectively relieve symptoms of seasonal allergic rhinitis (SAR). OBJECTIVE: To compare the effects of fexofenadine hydrochloride, 180 mg, and cetirizine, 10 mg, on symptoms, drowsiness, and motivation in patients with moderate-to-severe SAR. METHODS: In this 2-week multicenter, double-blind, randomized study, 495 subjects with moderate-to-severe SAR received once-daily fexofenadine hydrochloride, 180 mg, or cetirizine, 10 mg, without regard to food intake. Daily 12-hour reflective (AM, PM) and instantaneous (AM) individual symptoms and total symptom score (TSS) were evaluated. Drowsiness and motivation were recorded daily using visual analog scale at 7 AM, 10 AM, and 3 PM. RESULTS: Between-treatment differences in reduction from baseline in AM instantaneous and 24-hour reflective TSS were -0.18 [95% confidence interval (CI), -0.55 to 0.20) and -0.22 (95% CI, -0.59 to 0.15), respectively. Since CIs for reduction in TSS between treatments fell within a 0.7 margin (defined a priori), treatments were considered statistically equivalent. Patients receiving fexofenadine experienced significantly less overall drowsiness vs baseline than those receiving cetirizine [-2.33 (95% CI, -3.80 to 0.86) vs 0.37 (95% CI, -1.10 to 1.84), P = .0110]. There was a trend toward greater improvements in overall motivation with fexofenadine compared with cetirizine [-2.36 (95% CI, -3.83 to 0.90) vs -0.30 (95% CI, -1.76 to 1.17), P = .0504]. CONCLUSIONS: Once-daily fexofenadine hydrochloride, 180 mg, given for 2 weeks caused statistically and clinically equivalent improvement in symptoms and significantly less drowsiness va baseline, compared with cetirizine, 10 mg, in patients with moderate-to-severe SAR.

Efficacy and safety profile of fexofenadine HCl: a unique therapeutic option in H1-receptor antagonist treatment.

Results of head-to-head comparative trials suggest that fexo-fenadine might offer distinct advantages compared with other antihistamines. Fexofenadine is highly selective for peripheral H(1)-receptors and does not cross the blood-brain barrier, as shown by positron emission tomography. These data support findings that fexofenadine is nonsedating and does not impair performance or driving ability, even at very high doses. In addition, fexofenadine does not interact with muscarinic receptors, which might offer a potential advantage compared with desloratadine, the recently approved active metabolite of loratadine. Fexofenadine is devoid of adverse cardiac effects, and changes in electrocardiogram parameters are not significantly different from those observed with placebo. Fexofenadine has also been shown to have a favorable effect on nasal congestion. This therapeutic advantage might be related to its significant antiallergic properties, ie, the demonstrated ability of fexofenadine to blunt the inflammatory effects of preformed and de novo synthesized mediators at clinically relevant doses in vivo and in vitro. Cumulatively, these benefits distinguish fexofenadine from other antihistamines and make it an optimum therapeutic option for treating allergy-mediated respiratory and dermatologic diseases.

Relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo using a skin test model of wheal-and-flare suppression.

BACKGROUND: H1-receptor antagonists differ in their ability to produce peripheral H1-blockade. Suppression of histamine-induced flares and wheals is a useful objective test for measuring these differences. OBJECTIVE: To evaluate the relative potency of fexofenadine HCI 180 mg, loratadine 10 mg, and placebo (PBO) in suppressing histamine-induced flares and wheals and compare the onset, duration, and maximum suppression of histamine achieved with each agent. METHODS: Thirty healthy volunteers were enrolled in this randomized, double-blind, single-dose, crossover study. Flares and wheals induced by skin-prick testing with histamine 1.8 mg/mL were measured before treatment, every 20 minutes during the first hour after dosing, and thereafter hourly between 2 and 12 hours and between 23 and 25 hours postdose. RESULTS: Fexofenadine was significantly more effective than loratadine in suppressing the histamine-induced flare response at hours 2 through 7 and 10 through 12 and produced greater flare suppression than did PBO at hours 2 through 25. Onset of flare suppression occurred 2 hours after dosing with fexofenadine and 4 hours after dosing with loratadine. Likewise, fexofenadine was superior to loratadine in suppressing the wheal response from hours 1 through 12 and was more effective than PBO at hours 1 through 12, 24, and 25. Throughout the 25-hour measurement interval, the magnitude of difference in both wheal and flare suppression consistently favored fexofenadine over loratadine. CONCLUSIONS: In a skin test model of wheal-and-flare suppression, fexofenadine showed rapid distribution into the skin compartment with faster onset of action and greater potency vs loratadine.

Effects of fexofenadine, diphenhydramine, and placebo on performance of the test of variables of attention (TOVA).

OBJECTIVE: To determine the effects of diphenhydramine 50 mg and fexofenadine 180 mg on cognitive performance using the Test of Variables of Attention (TOVA), and to ascertain whether the TOVA was sufficiently sensitive to differentiate between the effects of these first- and second-generation H1-receptor antagonists on performance. STUDY DESIGN: The study used a double-blind, placebo-controlled, randomized, crossover design. Forty-two subjects completed four separate TOVA tests: at baseline and after administration of placebo, diphenhydramine 50 mg, and fexofenadine 180 mg. On each occasion, subjects rated subjective feelings of drowsiness on a visual analog scale (VAS) before taking the TOVA. RESULTS: Compared with placebo, diphenhydramine caused an increased response time (P = 0.0230) and more omission errors (P = 0.0398). Diphenhydramine was also associated with increased drowsiness VAS ratings (P = 0.0065) compared with placebo. Diphenhydramine caused significantly more commission errors than fexofenadine (P = 0.0354). Neither placebonor fexofenadine 180 mg caused significant changes in any TOVA or VAS measurements compared with baseline. Fexofenadine was not statistically different from placebo for any evaluation. CONCLUSIONS: The TOVA was sufficiently sensitive to differentiate between the central nervous system effects of fexofenadine and diphenhydramine. Fexofenadine 180 mg had no significant effect on the TOVA measures of performance or on self-reported drowsiness compared with placebo. In contrast, diphenhydramine 50 mg caused significant increases in omission errors and response time on the TOVA and increases in self-reported drowsiness compared with placebo [corrected].