Safety of desloratadine syrup in children

SUMMARY

Background: Allergic rhinitis (AR) and acute urticaria are common childhood maladies. Typically, the first-line treatment options for both include non-sedating antihistamines. First-generation antihistamines, such as diphenhydramine and hydroxyzine, although useful, cause sedation. Desloratadine, an oral non-sedating antihistamine, has been shown in multiple studies to be safe and effective in relieving the symptoms of AR and chronic idiopathic urticaria (CIU) in adults and adolescents.

Objective and methods: The current double-blind, placebo-controlled, parallel-group, single-center studies were undertaken to determine the safety and tolerability of desloratadine syrup in children aged 2?years–11?years with AR or CIU. Over 14 days, subjects aged 2?years–5?years were randomly assigned to receive once a day either 1.25?mg of desloratadine syrup (0.5?mg/mL) or matching placebo, and subjects aged 6?years–11?years were randomly assigned to receive once a day either 2.5?mg of desloratadine syrup or matching placebo. Safety evaluations included adverse event report collection, monitoring of vital signs, clinical laboratory measurements, and standard 12-lead electrocardiogram (ECG) measurements.

Results: In the study involving subjects aged 2?years–5?years (n = 111), the incidence of adverse events was 7/55 for the group treated with desloratadine and 6/56 for placebo. In the study involving subjects aged 6?years–11?years (n = 120), the incidence of adverse events was 1/60 for the group treated with desloratadine and 6/60 for placebo. No severe or serious adverse events occurred, and no clinically relevant changes were noted in median clinical laboratory test values or mean vital signs in either group. ECG results from both age groups demonstrated no significant changes (?p = NS) in mean ventricular rate or PR, QRS, or QT. No subjects had a Fridericia QT_c interval > 440?ms at day 8 or day 15.

Conclusion: These studies demonstrate the safety of desloratadine syrup in children aged 2?years–11?years with AR or CIU.     

Post-bedtime dosing with indiplon in adults and the elderly: results from two placebo-controlled,active comparator crossover studies in healthy volunteers

ABSTRACT

Objective: To assess the effects of post-bedtime dosing with indiplon on next-day function in adults and the elderly.

Research design and methods: Two randomized, double-blind, placebo-controlled crossover studies were conducted in two groups of healthy volunteers: an adult study (18–45 years) and an elderly study (65–80 years). In adults, a single post-bedtime dose of indiplon 10?mg and 20?mg was compared to placebo, with zolpidem 10?mg and zopiclone 7.5?mg included as controls. In the elderly, a single post-bedtime dose of indiplon 5?mg and 10?mg was compared to placebo, with zopiclone 3.75?mg included as a control. Next-day residual effects were evaluated in the morning at 4 and 6?h post-dose in adults, and 4, 6, and 8?h in the elderly, by a Visual Analog Scale of sleepiness (VAS-sleepiness), Digit Symbol Substitution Test (DSST), and the Symbol Copying Test (SCT).

Results: In adults, there were no statistically significant differences between indiplon and placebo on the VAS-sleepiness, DSST, or SCT at any timepoint for either dose. In contrast, a significant increase versus placebo in VAS-sleepiness was observed for both zopiclone (at 4 and 6?h post-dose; p < 0.0001 and p = 0.002, respectively) and zolpidem (at 4?h post-dose; p = 0.042). In the elderly, there were no statistically significant differences between indiplon 5?mg and placebo on the VAS-sleepiness, DSST, or SCT at any timepoint. DSST was significantly reduced for indiplon 10?mg versus placebo at 4?h only (?p = 0.022), compared with a significant reduction in DSST for zopiclone at both 4 and 8?h post-dose (?p = 0.002 and p = 0.003, respectively). In adults, the overall incidence of adverse events was higher on zopiclone compared to indiplon, zolpidem, and placebo. In the elderly, the incidence of adverse events was similar for indiplon, zopiclone, and placebo. Potential limitations of the current study include recruitment of healthy volunteers and the use of a limited pharmacodynamic battery.

Conclusions: Indiplon, at doses of 10?mg in adults and 5?mg in the elderly, was not associated with next day residual sedation or impairment in simple cognitive and psychomotor tasks when administered during the night 4?h prior to awakening.     

Comparative efficacy of bilastine,desloratadine and rupatadine in the suppression of wheal and flare response induced by intradermal histamine in healthy volunteers

Objective: To compare the peripheral antihistaminic activity of bilastine, rupatadine and desloratadine in inhibiting the histamine-induced wheal and flare (W&;F) response.

Research design and methods: Twenty-four healthy volunteers aged 18–40 years participated in this crossover, randomized, double-blind, placebo-controlled clinical study. Subjects received single doses of bilastine 20?mg, desloratadine 5?mg, rupatadine 10?mg and placebo. W&;F responses induced by intradermal injection of histamine 5?μg were evaluated before treatment (basal value) and at 0.5, 1, 2, 4, 6, 9, 12 and 24?hours after treatment. Fifteen minutes after histamine injection, W&;F surface areas (cm²) were quantified using the Visitrak System. Itching sensation was evaluated using a 100?mm visual analog scale.

EudraCT number: 2015-000790-13.

Main outcome measures: The primary outcome measure was the percentage reduction in W&;F areas after each active treatment compared with corresponding basal values.

Results: Bilastine induced the greatest inhibition in wheal area and was significantly superior to desloratadine and rupatadine from 1 to 12?hours (both p?p?p?p?Conclusions: Bilastine 20?mg induced significantly greater inhibition of the W&;F response compared with desloratadine 5?mg and rupatadine 10?mg throughout the 24?hour study period, and had the fastest onset of action. Only bilastine significantly reduced itching sensation versus placebo.     

The effects of cimetidine and ranitidine on psychomotor function in healthy volunteers

Summary

Single oral doses of cimetidine (400?mg), ranitidine (150?mg), promethazine (25?mg) or placebo were administered to 8 healthy volunteers in a double-blind study. Cimetidine and ranitidine did not cause any significant change in critical flicker frequency (c.f.f.), reaction time, pursuit rotor or the visual analogue scale scores for sedation. Promethazine significantly lowered c.f.f., prolonged reaction time and increased sedation when compared with placebo. It is concluded that in this study cimetidine and ranitidine had little, if any, effect on psychomotor function.     

The Effects of Single and Repeated Administration of Ebastine on Cognition and Psychomotor Performance in Comparison to Triprolidine and Placebo in Healthy Volunteers

Summary

Objective:The cognitive and psychomotor effects of 10?mg, 20?mg and 30?mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10mg (as averum) and placebo in 10 healthy volunteers in a double-blind, randomised crossover study.

Methods: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1?h, 2?h, 4?h and 8?h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ).

Results: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p?<?0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the I difference with placebo reaching statistical significance on day 1,8?h post-dose (p?<?0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8?h on day 1 (p?<?0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4?h and 8?h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2?h and 4?h following triprolidine administration on day 1 and ebastine (30?mg) was rated as sedative 4?h following administration on day 5. The perceived sedative activity of ebastine 30?mg was also reflected in the subjective reports on the LSEQ on day 1 (p?<?0.05).

Conclusions: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10–20?mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10?mg.     

Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia*

ABSTRACT

Objective: This study evaluated the long-term safety and tolerability of ezetimibe/simvastatin coadministration therapy compared to simvastatin monotherapy in patients with primary hypercholesterolemia.

Research design and methods: After completing a 12-week randomized, double-blind, placebo-controlled, factorial, 10-armed study comparing ezetimibe 10?mg/simvastatin 10, 20, 40, or 80?mg; simvastatin 10, 20, 40, or 80?mg; ezetimibe 10?mg; or placebo, 768 patients entered a 48-week extension, with randomized, blinded, reassignment of the simvastatin 10?mg, ezetimibe, and placebo groups to one of the ezetimibe/simvastatin groups. Patients previously receiving ezetimibe/simvastatin combination therapy, or simvastatin 20, 40, and 80?mg monotherapy continued the same therapies in this 7-arm extension study. During the extension study, investigators assessed adverse events (AEs).

Main outcome measures and results: Ezetimibe/simvastatin (n?=?539) and simvastatin monotherapy (n?=?229) groups generally had a similar incidence of all clinical AEs (73 vs. 69%), treatment-related AEs (14 vs. 11%), clinical serious AEs (SAE) (5.2 vs. 2.6%), treatment-related SAEs (0.2 vs. 0%), discontinuations due to all clinical AEs (4.5 vs. 2.6%) and discontinuations due to treatment-related AEs (2.8 vs. 2.2%), respectively. The incidence of total laboratory-related AEs for the ezetimibe/simvastatin and simvastatin monotherapy groups was also similar (12.2 vs. 11.9%), as was treatment-related laboratory AEs (6.2 vs. 5.3%), laboratory SAEs (0 vs. 0%), treatment-related laboratory SAEs (0 vs. 0%), discontinuations due to laboratory AEs (3.0 vs. 0.9%) and discontinuations due to treatment-related laboratory AEs (3.0 vs. 0.4%), respectively. There were no cases of myopathy, rhabdomyolysis, or serious hepatotoxicity observed in any group during this extension study.

Conclusions: During this 48-week extension study, the coadministration of ezetimibe/simvastatin was generally as well tolerated as simvastatin monotherapy. The direct application of study observations to clinical practice is limited by patient selection criteria and dosage regime, which randomly applied relatively high doses rather than titration which often occurs in clinical practice.     

Efficacy and safety of rofecoxib 12.5 mg and celecoxib 200 mg in two similarly designed osteoarthritis studies

ABSTRACT

Objective:?To compare the lower osteoarthritis (OA) dose of rofecoxib to the recommended dose of celecoxib in two identically designed studies.

Methods:?Patients with knee OA were randomized (2:2:1 ratio: rofecoxib 12.5?mg once daily (qd), celecoxib 200?mg qd, or placebo, respectively). The primary endpoint was patient global assessment of response to therapy (PGART) averaged over 6 weeks on a five-point scale. Rofecoxib would be declared at least as effective as celecoxib if the lower bound of the 95% confidence interval (95% CI) for difference in means was no lower than –0.5. Additional endpoints included Pain and Physical Function subscales of the Western Ontario and McMaster (WOMAC) OA Index. Adverse experiences (AEs) were recorded and combined from the two studies for analysis.

Results:?Study 1 enrolled 395 patients (rofecoxib, n = 160; celecoxib, n = 157; placebo, n = 78). Study 2 enrolled 413 patients (rofecoxib, n = 159; celecoxib, n = 169; placebo, n = 85). Rofecoxib 12.5?mg was at least as effective as celecoxib 200?mg by PGART (Study 1 difference –0.09 [95% CI: –0.32, 0.14] and Study 2 difference 0.02 [95% CI: –0.20, 0.24]), and both were significantly (?p < 0.001) more effective than placebo. Comparable efficacy was also seen for WOMAC Pain and Physical Function subscales with the active treatments. There was a significantly higher (?p < 0.05) incidence of serious AEs with celecoxib than rofecoxib or placebo, none of which was drug-related. There were no significant differences in the pre-specified measurements of safety including drug-related AEs or discontinuations due to AEs, and the medications demonstrated similar safety as assessed by spontaneous reporting.

Conclusions:?Rofecoxib 12.5?mg and celecoxib 200?mg provided comparable efficacy over 6 weeks, and both were significantly more efficacious than placebo. The medications demonstrated similar safety compared to one another and placebo. The primary limitations of these studies were that they were only 6 weeks long and were powered for efficacy. Therefore, conclusions about long-term safety cannot be inferred.     

Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia

SUMMARY

Objective: Eszopiclone is a new, single-isomer, non-benzodiazepine, cyclopyrrolone agent under investigation for the treatment of insomnia. The present study was a randomized, double-blind, multicenter, placebo-controlled trial conducted to assess the efficacy and safety of eszopiclone in adults with chronic primary insomnia.

Research design and methods: Patients (n = 308) were randomized to receive placebo or eszopiclone (2?mg or 3?mg) for 44 consecutive nights, followed by 2 nights of single-blind placebo. Efficacy was evaluated with polysomnography (Nights 1, 15 and 29) and patient-reports (Nights 1, 15, 29 and 43/44). Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST).

Results: Eszopiclone 3?mg had significantly less time to sleep onset (?p ≤ 0.0001), more total sleep time and sleep efficiency (?p ≤ 0.0001), better sleep maintenance (p ≤ 0.01), and enhanced quality and depth of sleep (?p < 0.05) across the double-blind period compared with placebo. Eszopiclone 2?mg had significantly less time to sleep onset (?p ≤ 0.001), more total sleep time (?p ≤ 0.01) and sleep efficiency (?p ≤ 0.001), and enhanced quality and depth of sleep (?p < 0.05) compared with placebo, but did not significantly improve sleep maintenance. There was no evidence of tolerance or rebound insomnia after therapy discontinuation. Median DSST scores showed no decrement in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group. Treatment was well tolerated; the most common adverse event related to eszopiclone was unpleasant taste.

Conclusions: Patients treated with nightly eszopiclone 3?mg had better polysomnographic (through Night 29) and patient-reported measures (through Night 44) of sleep over the 6-week trial. There was no evidence of tolerance or rebound insomnia and no detrimental effects on next-day psychomotor performance using the DSST.     

Desloratadine

Desloratadine is the orally active major metabolite of the nonsedating H1-antihistamine loratadine. The drug had no adverse cardiovascular effects in various animal models or when administered at 9 times the recommended adult dosage for 10 days in volunteers. Therapeutic dosages had no effects on wakefulness or psychomotor performance in healthy volunteers. No clinically significant interactions have been reported between desloratadine and drugs that inhibit the cytochrome P450 system, nor does the drug potentiate the adverse psychomotor effects of alcohol. Oral desloratadine 5 mg once daily for up to 4 weeks in patients with seasonal allergic rhinitis (SAR) significantly reduced nasal (including congestion) and non-nasal symptoms and improved health-related quality of life compared with placebo. Similar beneficial effects were observed in patients with SAR and coexisting asthma (in whom asthma symptoms and use of beta2-agonists were reduced). Desloratadine 5 mg once daily for 6 weeks significantly improved pruritus and reduced the number of hives compared with placebo in patients with chronic idiopathic urticaria (CIU). Sleep and daytime performance also improved. Desloratadine was well tolerated in clinical trials and had an adverse event profile similar to that of placebo in patients with SAR (with or without asthma) or CIU.     

Effects of desloratadine,diphenhydramine, and placebo on driving performance and psychomotor performance measurements

Introduction First-generation antihistamines taken for relief of allergic rhinitis are sedating and pose potential risks for those driving a car or operating machinery. Desloratadine is a potent, selective, histamine H₁-receptor antagonist that does not easily cross the blood–brain barrier. It is nonsedating at therapeutic doses and should not affect driving or psychomotor performance.Objective This study compared the acute effects of desloratadine with diphenhydramine (active control) and placebo on the performance of healthy subjects evaluated with standard over-the-road driving tests (primary objective). The subjects performances were also evaluated (secondary objective) with the use of conventional performance tests.Methods Eighteen men and women received a single dose of desloratadine 5 mg, diphenhydramine 50 mg, or placebo during each period of this randomized, double-blind, three-way, crossover study. Two hours post-dosing, subjects operated a specially instrumented vehicle in a 90-min test designed to measure their ability (1) to maintain constant speed and lateral position while following another vehicle at a constant distance and (2) to respond to brake signals. Additionally, a full battery of performance tests was administered.Results No significant differences were noted between desloratadine and placebo in standard deviation of lateral position (SDLP), whereas diphenhydramine treatment significantly increased SDLP (P<0.001 for both comparisons). Brake reaction time was significantly faster following treatment with desloratadine than diphenhydramine (473.72 ms vs 541.22 ms; P<0.001) or placebo (512.06 ms; P=0.033). No differences were seen among treatments in deviation of speed or distance to the lead car. The majority of performance tests showed no significant differences among groups.Conclusion Desloratadine at a therapeutic dose does not impair driving performance.     

Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13‐week,randomized trial

ABSTRACT

Objective: This trial evaluated the efficacy and safety of pregabalin dosed twice daily (BID) for relief of neuro-pathic pain associated with postherpetic neuralgia (PHN).

Research design and methods: The 13‐week, double-blind, placebo-controlled study randomized 370 patients with PHN to pregabalin (150, 300, or 600?mg/day BID) or placebo.

Main outcome measures: Primary efficacy measure was endpoint mean pain score from daily pain diaries. Secondary efficacy measures included endpoint mean sleep-interference score from daily sleep diaries and Patient Global Impression of Change (PGIC). Safety evaluations included adverse events (AEs), physical and neurologic examinations, 12-lead ECG, vital signs, and laboratory testing.

Results: Pregabalin provided significant, dose-proportional pain relief at endpoint: difference from placebo in mean pain score, 150?mg/day, –0.88, p = 0.0077; 300?mg/day, –1.07, p = 0.0016; 600?mg/day, –1.79, p = 0.0003. Weekly mean pain scores significantly improved as early as week 1. Sleep interference in all pregabalin groups was also significantly improved at endpoint, compared with placebo (?p < 0.001), beginning at week 1 (?p < 0.01). At study termination, patients in the 150 (p = 0.02) and 600?mg/day (p = 0.003) groups were more likely to report global improvement than were those in the placebo group.

Most AEs were mild or moderate. Among pregabalin-treated patients, 13.5% withdrew due to AEs, most commonly for dizziness (16 patients, 5.8%), somnolence (8, 2.9%), or ataxia (7, 2.5%).

Conclusions: Pregabalin, dosed BID, reduced neuropathic pain associated with PHN and was well tolerated. It also reduced the extent to which pain interfered with sleep. Pregabalin's effects were seen as early as week 1 and were sustained throughout the 13‐week study.     

Non-sedating antihistamines in the treatment of chronic idiopathic urticaria using patient-reported outcomes

ABSTRACT

Background: Chronic idiopathic urticaria (CIU) greatly impairs quality of life (QoL). Thus, patient-reported outcome (PRO) measures, using validated scoring instruments, are probably the most accurate tools available for assessing the efficacy of medications that treat CIU, such as second-generation antihistamines.

Research methods: A structured search of the MEDLINE database was conducted to identify English-language papers published between 1 January 1991 and 30 September 2007 on the treatment of CIU with the second-generation antihistamines cetirizine, desloratadine, fexofenadine, and levocetirizine, and their effects on patient-reported QoL. We used the following search terms alone or in combination: ‘chronic idiopathic urticaria’; ‘pruritus’; ‘wheals’; ‘hives’; ‘second-generation antihistamines’; ‘cetirizine’; ‘desloratadine’; ‘fexofenadine’; ‘levocetirizine’; and ‘quality of life’.

Scope: We evaluated the effects of second-generation antihistamines on the QoL of subjects with CIU using desloratadine as a treatment model. Desloratadine was selected because it is the most frequently assessed non-sedating second-generation antihistamine in QoL studies in patients with CIU.

Findings: Desloratadine 5?mg QD improved QoL in numerous PRO studies. Treatment with desloratadine significantly (p?<?0.05) lowered (better) scores in three studies (n?=?364) that used validated dermatology-specific scoring instruments. Three 6-week double-blind, placebo-controlled trials (n?=?553) found that desloratadine significantly (p?<?0.05) improved patient-reported pruritus, sleep disruption, and interference with daily activities. Desloratadine was associated with a low incidence of adverse events and an overall tolerability profile similar to placebo.

Limitations: Limitations in this review include divergence in search practices that may lead to omission of relevant research, unintentional error in data transfer, inconsistency in quality of selected papers, and potential publication bias against papers that report results from small studies.

Conclusions: The favorable impact of second-generation antihistamines on the QoL of patients with CIU was demonstrated using desloratadine, the most frequently investigated drug in this field, as a treatment model.     

Systematic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever

ABSTRACT

Objective: The main aim of this review was to compare the tolerability and safety between ibuprofen and paracetamol when used as anti-pyretic and analgesic agents in children up to 18 years of age.

Methods: MEDLINE (1950 to November 2008), EMBASE (1980 to November 2008), The Cochrane Library (2007, Issue 3), ACP Journal Club (1991 to November 2007) and Pascal (1987 to November 2007) were searched for randomised controlled trails (RCTs) (comparing ibuprofen and/or paracetamol with placebo), controlled observational studies and large case series comprised more than 1000 participants.

Main outcome measures: Adverse events (AEs) requiring discontinuation of medication; systemic reactions related to ibuprofen or paracetamol; serious AEs that are fatal, life-threatening or require hospitalisation; and serious AEs not requiring hospitalisation.

Results: A total of 24 RCTs examined either ibuprofen and/or paracetamol versus placebo for AE data. Twelve other studies meeting our criteria were also included for AE data. Meta-analysis of systemic reactions demonstrated that tolerability and safety of ibuprofen was similar to placebo, as was paracetamol: ibuprofen versus placebo relative risk (RR) 1.39 (95% CI: 0.92, 2.10); paracetamol versus placebo RR 1.57 (95% CI 0.74, 3.33). A total of 2937 systemic AEs occurred in 21?305 patients taking ibuprofen compared with 1466 systemic AEs in 11?164 patients taking paracetamol: RR 1.03 (95% CI 0.98, 1.10). There was no significant difference between the two groups. Narrative analysis of AE data identified conflicting evidence regarding hepatic injury with paracetamol and group A streptococcal infections with ibuprofen or paracetamol treatment.

Conclusions: Ibuprofen, paracetamol and placebo have similar tolerability and safety profiles in terms of gastrointestinal symptoms, asthma and renal adverse effects. While the study data investigated here may not reflect over-the-counter use, these results are still relevant in the context of any safety concerns relating to general ibuprofen or paracetamol treatment in children.     

A 12-week,randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain

ABSTRACT

Objective: Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP).

Design and methods: Patients ≥ 18 years of age were titrated with oxymorphone ER (5- to 10?mg increments every 12?h, every 3–7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12?h for 12 weeks. Oxymorphone immediate release was available every 4–6?h, as needed, for the first 4 days and twice daily thereafter.

Results: Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4?mm at screening to 22.7?mm (?p < 0.0001). After random­ization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (?p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 ± 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 ± 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group.

Conclusions: Stabilized doses of oxymorphone ER were generally safe and effective over a 12?week double-blind treatment period in opioid-naive patients with CLBP.     

Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week,phase 3 study

Objective:

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam are commonly used to treat osteoarthritis (OA) but are associated with potentially serious dose-related adverse events (AEs). SoluMatrix meloxicam has been developed with the goal of enabling effective treatment at low doses. This phase 3 study evaluated the efficacy and safety of low-dose SoluMatrix meloxicam capsules 5?mg and 10?mg administered once daily for 12 weeks in patients with OA-related pain.

Research design and methods:

This randomized, double-blind study enrolled patients ≥40 years of age with confirmed hip or knee OA (Kellgren–Lawrence grade II–III) who were chronic users of NSAIDs and/or acetaminophen for OA pain and had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale mean scores ≥40?mm. Eligible patients experienced an OA pain flare (defined as a ≥15?mm increase in the WOMAC pain subscale score) following discontinuation of NSAIDs/acetaminophen. Patients were randomized to receive once-daily SoluMatrix meloxicam 5?mg or 10?mg, or placebo for 12 weeks.

ClinicalTrials.gov identifier: NCT01787188.

Main outcome measures:

The primary outcome measure was the mean change from baseline in WOMAC pain subscale score at week 12.

Results:

Low-dose SoluMatrix meloxicam 5?mg (?36.52 [2.49]; P?=?0.0005) and 10?mg (?34.41 [2.68]; P?=?0.0059) once-daily treatment significantly reduced the mean (standard error) WOMAC pain subscale score from baseline at week 12 compared with placebo (?25.68 [2.64]). Patients treated with SoluMatrix meloxicam 5?mg or 10?mg reported significantly greater improvements in total WOMAC score and in WOMAC stiffness and function subscale scores at 12 weeks compared with placebo. The most common AEs in the combined low-dose SoluMatrix meloxicam group were headache, diarrhea, nausea, osteoarthritis, and urinary tract infection.

Conclusions:

Low-dose SoluMatrix meloxicam may have a potential role as a new therapeutic option for the management of OA-related pain.     

A 2-night, 3-period,crossover study of ramelteon's efficacy and safety in older adults with chronic insomnia

ABSTRACT

Objective: To assess the efficacy and safety of ramelteon, a selective melatonin MT₁/MT₂-receptor agonist, for insomnia treatment in older adults.

Methods: In a randomized, 9?week, 3?period crossover trial conducted at 17 sleep centers, older adults (N = 100) with chronic primary insomnia (37 men, 63 women; mean age [range], 70.7 [65–83] years) were administered placebo, ramelteon 4?mg, and ramelteon 8?mg in three treatment phases for two consecutive nights. Each phase was separated by 5- to 12?day washout periods. Sleep was monitored via polysomnography. Subjective sleep parameters, using a Postsleep Questionnaire, were recorded, and residual pharmacologic effects were assessed.

Results: Statistically significant reductions in latency to persistent sleep were observed with both ramelteon 4?mg and 8?mg compared to placebo (28.7?min vs. 38.4?min, p < 0.001; 30.8?min vs. 38.4?min, p = 0.005, respectively). Total sleep time (p = 0.036 and p = 0.007,respectively) and sleep efficiency (p = 0.037 and p = 0.007, respectively) were also significantly improved with ramelteon 4?mg and 8?mg compared to placebo. Statistically significant reductions in subjective sleep latency on a Postsleep Questionnaire were reported with ramelteon 4?mg versus placebo (p = 0.037), but not ramelteon 8?mg (p = 0.120); no significant differences on other subjective sleep assessments were reported. A lack of power limits interpretation of self-reported sleep parameters. Incidences of adverse events considered treatment related were placebo (7%), ramelteon 4?mg (11%), and ramelteon 8?mg (5%). No residual pharmacologic effects were observed via Digit Symbol Substitution Test, memory recall tests (immediate and delayed), visual analog scales (feelings and mood), and Postsleep Questionnaire (level of alertness and ability to concentrate).

Conclusions: In older adults with chronic primary insomnia, ramelteon produced significant reductions in latency to persistent sleep and increases in total sleep time and sleep efficacy, and showed no evidence of adverse next-day psychomotor or cognitive effects.     

Rofecoxib 12.5 mg,rofecoxib 25 mg,and celecoxib 200 mg in the treatment of symptomatic osteoarthritis: results of two similarly designed studies

ABSTRACT

Objective: To compare the efficacy of rofecoxib and celecoxib for the treatment of knee or hip OA over 6 weeks.

Methods: Two similarly designed, multicenter, randomized, double-blind, placebo-controlled studies. Patients were randomly assigned 3:3:3:1 in Study 1 to once daily (QD) rofecoxib 12.5?mg (N = 456), rofecoxib 25?mg (N = 459), celecoxib 200?mg (N = 456), or placebo (N = 150) and 3:3:1 in Study 2 to QD rofecoxib 25?mg (N = 471), celecoxib 200?mg (N = 460), or placebo (N = 151). There was no rofecoxib 12.5?mg arm in Study 2. The primary outcome measure of both studies was pain at night over 6 weeks for rofecoxib 25?mg vs. celecoxib 200?mg. Efficacy comparisons with rofecoxib 12.5?mg in Study 1 were included as pre-specified study objectives but not as pre-specified study hypotheses. Secondary endpoints included Patient Global Assessment of Response to Therapy (PGART) over 6 weeks and over 1 week. Safety was evaluated through the assessment of spontaneously reported adverse experiences (AEs), evaluation of vital signs, and laboratory data reported by investigators and patients.

Results: For the primary endpoint, reduction in pain at night over 6 weeks in Study 1 was not significantly different between active treatments; in Study 2 rofecoxib 25?mg significantly (?p = 0.023) reduced pain at night compared with celecoxib 200?mg over 6 weeks. For the secondary endpoints, in both studies, significantly (?p < 0.05) more patients treated with rofecoxib 25?mg than celecoxib 200?mg had a good or excellent PGART over 6 weeks, and over the first week (?p < 0.01). In both studies, there were no significant differences between active medications in the incidence of reported overall, serious, or drug-related AEs. The reported AE rates with the active treatments were generally similar to those with placebo in the two studies.

Conclusions: Rofecoxib 25?mg was significantly better than celecoxib 200?mg in relieving night pain at 6 weeks in one study; this was not confirmed in the accompanying study.     

The effect of fluvastatin on the pharmacokinetics and pharmacodynamics of ezetimibe

ABSTRACT

Objective: The objective of this study was to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and fluvastatin in healthy hypercholesterolemic subjects at clinically-relevant doses and to evaluate the potential for a pharmacokinetic drug interaction between ezetimibe and fluvastatin.

Methods: In a single-center, evaluator-blind, placebo-controlled, multiple-dose, parallel-group study 32 healthy subjects with hypercholesterolemia were randomized to 4 treatments administered once daily for 14 days: ezetimibe 10?mg plus ezetimibe placebo, fluvastatin 20?mg plus ezetimibe placebo, fluvastatin 20?mg plus ezetimibe 10?mg, and ezetimibe placebo. Blood samples were collected to measure serum lipids and to determine steady-state pharmacokinetics.

Results: Ezetimibe 10?mg significantly (?p ≤ 0.01) decreased total-cholesterol and low-density lipoprotein cholesterol (LDL‐C) concentrations compared to placebo at Day 14. Fluvastatin 20?mg also caused a significant (?p = 0.01) reduction in total-cholesterol and a decrease in LDL‐C at Day 14 compared to placebo, however, the decrease in LDL‐C did not reach statistical significance (?p = 0.08). The coadministration of ezetimibe 10?mg and fluvastatin 20?mg caused significantly (?p ≤ 0.01) greater mean percent reductions in LDL‐C and total-cholesterol than fluvastatin 20?mg alone or placebo at Day 14. Fluvastatin had no clinically significant effect on the pharmacokinetics of ezetimibe. On average, ezetimibe appeared to decrease the rate and extent of fluvastatin bioavailability.

Conclusion: Coadministration of ezetimibe and fluvastatin was safe and well tolerated and caused significant incremental reductions in LDL‐C and total cholesterol compared to fluvastatin administered alone. The pharmacokinetics of ezetimibe were not affected by coadministration with fluvastatin. The apparent decrease in fluvastatin exposure on administration with ezetimibe was likely to be due to the parallel study design and two pharmacokinetic outliers and is considered of no clinical significance.     

Bilastine vs. hydroxyzine: occupation of brain histamine H1-receptors evaluated by positron emission tomography in healthy volunteers

AimA close correlation exists between positron emission tomography (PET)-determined histamine H₁-receptor occupancy (H₁RO) and the incidence of sedation. Antihistamines with H₁RO <20% are classified as non-sedating. The objective was to compare the H₁RO of bilastine, a second generation antihistamine, with that of hydroxyzine.MethodsThis randomized, double-blind, crossover study used PET imaging with [¹¹C]-doxepin to evaluate H₁RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H₁ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated.ResultsThe mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H₁RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine.ConclusionsA single oral dose of bilastine 20 mg had minimal H₁RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.     

Pharmacodynamic and pharmaco-kinetic interaction between fenofibrate and ezetimibe*

SUMMARY

Objective: The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia.

Research design and methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study. Subjects with untreated LDL-C ≥ 130?mg/dL (3.37?mmol/L) were randomized to receive one of four oral treatments each morning for 14?days: fenofibrate 200?mg + ezetimibe 10?mg, fenofibrate 200?mg, ezetimibe 10?mg, or placebo. Serum lipids were assessed before drug administration on day 1, day 7, and day 14. Pharmacokinetic parameters were assessed on day 14.

Main outcome measures: The primary pharmacodynamic parameter was percentage change from baseline in LDL-C concentration following co-administration of ezetimibe and fenofibrate vs either drug alone, or placebo. A secondary outcome was the potential for a pharmacokinetic interaction between ezetimibe and fenofibrate.

Results: Ezetimibe and fenofibrate co-administration was well tolerated and produced statistically significant mean percentage reductions from baseline in LDL-C (?p ≤ 0.05 vs either drug alone or placebo), total cholesterol and triglycerides (?p ≤ 0.05 vs either fenofibrate or placebo), apolipoprotein C-III (?p ≤ 0.05 vs placebo), and LDL-III (?p ≤ 0.05 vs either drug alone or placebo). Ezetimibe did not significantly affect the pharmacokinetics of fenofibrate. Concomitant fenofibrate administration significantly increased the mean C_max and AUC of total ezetimibe approximately 64% and 48%, respectively. However, based on the established safety profile and flat dose-response of ezetimibe, this effect is not considered to be clinically significant.

Conclusion: Co-administration of ezetimibe and fenofibrate produced significantly greater reductions in LDL-C than either drug alone and greater reductions in triglycerides than fenofibrate. These effects were accompanied by improvements in the lipid/lipoprotein profile, suggesting that co-administration therapy with ezetimibe and fenofibrate may be an effective therapeutic option for patients with mixed dyslipidemia.