The Time Course of Effect of Multilayer-Release Methylphenidate Hydrochloride Capsules: A Randomized, Double-Blind Study of Adults With ADHD in a Simulated Adult Workplace Environment.

Objective: The aim of this study is to assess the onset and duration of efficacy of multilayer-release methylphenidate (PRC-063) over 16 hr compared with placebo in adults with ADHD using the simulated adult workplace environment. Method: After dose-optimization with PRC-063, participants entered a double-blind, placebo-controlled, crossover phase. Primary outcome measure was the Permanent Product Measure of Performance (PERMP) total score measured pre-dose and from 1 to 16 hr post-dose. Results: Of the 59 randomized participants, 45 participants completed the study. While receiving PRC-063, adults had greater mean PERMP total scores across all time points compared with placebo (268.7 ± 11.24 vs. 255.6 ± 10.87; p = .0064). Common adverse events were decreased appetite, headache, and insomnia. There was no significant impact on overall sleep quality (p = .9542). Conclusion: PRC-063 significantly improved PERMP scores with an onset within 1 hr post-dose, and maintained improvement throughout the 16 hr post-dose study period compared with placebo in adults with ADHD.

Abuse deterrence testing: A dose ratio escalation study examining naloxone coadministered with intravenous hydromorphone in non-treatment-seeking, opioid-dependent drug users.

OBJECTIVE: To assess the reduction in intravenous (IV) abuse potential of hydromorphone from different dose ratio combinations with naloxone in opioid-dependent drug users. DESIGN: Randomized, blinded, dose ratio escalation study. SETTING: Single center. PARTICIPANTS: Following conversion to a stable IV dose of hydromorphone, 12 non-treatment-seeking, opioid-dependent subjects were randomly assigned and received at least one dose of study drug; seven subjects received all five study treatments. Five subjects withdrew early from the treatment phase: adverse events (2) and participant decision (3). INTERVENTIONS: Participants underwent a dose-selection phase to stabilize on an individualized hydromorphone dose. Stable subjects were dosed intravenously on 5 consecutive days. The dose received was one of five hydromorphone/naloxone dose ratios that included the combination of hydromorphone and placebo naloxone. Hydromorphone/naloxone treatment always involved increasing dose ratios of naloxone (8:1, 6:1, 4:1, and 2:1) with the hydromorphone-placebo naloxone treatment randomly assigned within the sequence of dose ratios. MAIN OUTCOME MEASURES: Drug Liking visual analog scale (VAS), Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS). RESULTS: Hydromorphone/naloxone placebo produced subjective effects typical of opioid administration, while hydromorphone/naloxone dose ratios were associated with significant increases in SOWS and OOWS scores (p < 0.05). Compared with hydromoprophone/naloxone placebo, naloxone reduced the effects of hydromorphone on most measures, including Drug Liking VAS, the antagonism was greatest for the 4:1 and 2:1 ratios. CONCLUSIONS: This study was an ethical investigation of the abuse deterrence potential of four hydromorphone/naloxone dose ratios. The IV coadministration of commercially available IV solutions of hydromorphone and naloxone in 4:1 and 2:1 ratios had statistically greater reductions of abuse-related opioid effects and triggers of withdrawal symptoms and there was a convergence of subjective and objective pharmacodynamic results and safety findings. An oral modified-release product, developed with a 2:1 hydromorphone/naloxone ratio, may have important public health benefits by reducing high-risk, IV abuse of prescription opioids, while providing pain relief when ingested orally and used in accordance with the Product Monograph.

An evaluation of patient and physician satisfaction with controlled-release oxybutynin 15 mg as a one-step daily dose in elderly and non-elderly patients with overactive bladder: results of the STOP study.

OBJECTIVE: Evaluate patient and physician satisfaction with a novel formulation of a once-daily controlled-release (CR) oxybutynin (Uromax*) 15-mg tablet as both the initial and maintenance dose in elderly and non-elderly patients with overactive bladder (OAB). METHODS: Patients not on anticholinergic treatment for OAB and experiencing urinary incontinence (≥1 episode/week) and micturition frequency (≥8 episodes/day) or urgency (≥1 episode/week) were enrolled in this 4-week, open-label study. Satisfaction, efficacy, mental status and adverse events were evaluated by urologists, gynecologists, urogynecologists and family practitioners. The analyses compared the outcomes in patients <65 and ≥65 years. CLINICAL TRIAL REGISTRATION: ISRCTN 19242032. RESULTS: A total of 240 patients enrolled; 111 (46%) were ≥65 years of age. Completion rate was 76.0% (<65) and 62.2% (≥65) (p = 0.0204). Medication was rated as tolerable by 75.2% of patients <65 and 58.6% of patients ≥65 (p = 0.0099). Based on overall satisfaction scores 64.2% (patient scores) and 57.1% (physician scores) of patients were considered 'successfully treated' (p = 0.0001 & p = 0.0451). There was a significant reduction in incontinence (64.3%; p = 0.0001), nocturia (38.6%; p = 0.0001) and night-time incontinence (39.7%; p = 0.0436) with no difference between age groups. Total continence was achieved by 29.8% and 47.5% of patients <65 and ≥65, respectively (p = 0.0077). No patients clinically experienced confusion or delirium and only six patients ≥65 had a decrease in MMSE score of ≥3 units, which was not statistically different from patients <65 (p = 0.3112). Dry mouth was the most common adverse event reported by 24.8% of patients <65 and 36.0% of patients ≥65 (p = 0.0584). Limitations of the study include a fixed dosing, no control group and 4-week trial. CONCLUSION: Patients and physicians were satisfied with CR oxybutynin 15 mg once-daily. Patients tolerated the CR oxybutynin 15 mg as both the initial and maintenance dose and provided significant reductions in incontinence, nocturia and night-time incontinence without a significant change in cognitive status. Total continence rates were significantly superior in patients ≥65 and there was no difference in dry mouth, cognitive status or efficacy in patients <65 and ≥65.

Comparative bioavailability of single-dose methylphenidate from a multilayer-release bead formulation and an osmotic system: a two-way crossover study in healthy young adults.

OBJECTIVE: This study was conducted to compare plasma levels of methylphenidate over time with single doses of a multilayer-release (MLR) bead formulation and an osmotic, controlled-release oral delivery system (OROS) of methylphenidate in young adults. METHODS: This was a randomized, 2-way crossover study in which healthy, nonsmoking young adults (age 18-25 years) were randomized to receive methylphenidate MLR 20 mg QD or OROS methylphenidate 18 mg QD, with a 7-day washout between treatments. Plasma samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 16, and 24 hours after dosing. Analysis of plasma samples was conducted by high-performance liquid chromatography with tandem mass-spectrometry detection. Adverse events were monitored by spontaneous reports, laboratory and biochemistry tests, urinalysis, and physical examinations conducted at screening and at the end of the study. RESULTS: Of the 24 subjects originally enrolled, 3 discontinued for personal reasons after the first phase and were not included in the pharmacokinetic analysis. The per-protocol population (11 females, 10 males) had a mean (SD) age of 22 (2) years (range, 19-25 years) and a mean body mass index of 23.6 (3.0) kg/m(2) (range, 19.0-28.5 kg/m(2)). The relative AUC0t and Cmax ratios for the MLR methylphenidate formulation compared with the OROS methylphenidate formulation were 110.88% and 121.84%, respectively. When OROS methylphendate values were dose normalized to 20 mg, the relative AUC0-t and Cmax ratios were 100.72% and 111.82%. The mean Tmax for the 2 formulations was 3.71 (2.03) and 4.96 (2.56) hours. Values were significantly higher with the MLR methylphenidate formulation compared with the OROS methylphenidate formulation for AUC(0-4) (P < 0.001), AUC(0-8) (P < 0.001), AUC(0-12) (P < 0.001), and AUC(4-12) (P = 0.037); the AUC(8-12) was not significantly different between the 2 formulations. Values were significantly higher for the MLR methylphenidate formulation relative to the OROS methylphenidate formulation for C(max0-4) (P < 0.001) and C(max4-12) (P = 0.002). Thirty-seven adverse events occurred in 11 and 10 subjects during receipt of MLR and OROS methylphenidate, respectively. The most commonly reported adverse events in the intent-to-treat population were catheter-site pain, reported by 8 of 24 subjects (33.3%), and headache, reported by 5 of 24 subjects (20.8%). CONCLUSIONS: In these healthy young subjects, MLR methylphenidate was associated with a concentration-time profile that resulted in a higher proportion of the administered methylphenidate dose being delivered in the first 4 hours after dosing compared with OROS methylphenidate while maintaining comparable levels of drug in the latter portion of the dosing interval. This led to maintenance of higher mean levels of methylphenidate throughout the day compared with the closest marketed dose of OROS methylphenidate. The 2 formulations are marketed in dissimilar strengths; however, after correction for administered dose, they yielded similar AUC values.

Cognitive and behavioral effects of multilayer-release methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of this study was to compare the pharmacodynamics of a new multilayer-release (MLR) formulation methylphenidate (MPH; Biphentin) with immediate-release (IR) MPH (Ritalin) in a double-blind, cross-over, placebo-controlled study in patients with attention-deficit/hyperactivity disorder (ADHD). METHOD: Patients were randomized to equivalent doses of MPH as MLR (once per day), IR (twice per day) or placebo. Each treatment was taken for 1 week prior to repeated behavioral and cognitive laboratory evaluations on a single day in each phase of the crossover. RESULTS: Two girls and 15 boys 6.8-15.3 years old (mean age 11.3 +/- 2.2 years) participated. Both MLR and IR MPH significantly reduced the Stop Signal Reaction Time (p = 0.0001, p = 0.0005), the Errors of Omission on the Continuous Performance Task (p = 0.0039, p = 0.0001), the IOWA-Conners Inattention/Overactivity Index (p = 0.0001, p = 0.0001), and increased the Clinical Global Impressions (CGI) Efficacy Index (p = 0.0001, p = 0.0017) and reduced the CGI Global Improvement Index (p = 0.0001, p = 0.0006) compared to placebo. Mild adverse events were experienced by 4, 6, and 3 patients on placebo, IR, and MLR MPH, respectively. CONCLUSIONS: MLR MPH given once daily produces equivalent improvements in behavioral and cognitive measures, and has a duration of effect at least as long as that of IR MPH given twice daily.

Once-daily multilayer-release methylphenidate in a double-blind, crossover comparison to immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The purpose of this study was to evaluate the comparative efficacy and safety of a novel long-duration multilayer-release (MLR) methylphenidate (MPH) formulation and immediate-release (IR) MPH in attention-deficit/hyperactivity disorder (ADHD) children. PATIENTS AND METHODS: This study was a randomized, double-blind, crossover comparison of once-daily MLR and twice-daily IR-MPH in home and school settings in children with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of ADHD. Patients completed a 1-week baseline followed by two active medication titration phases. Each phase of treatment was 1-4 weeks of titration with an additional stable dose week. The final dose was based on efficacy and adverse events for each patient. Efficacy measures included Clinical Global Impressions (CGI) and Conners' Parent and Teacher Rating Scales (CPRS and CTRS). The Clinical Assessment of Side Effects (CASE) scale assessed frequency of adverse events. RESULTS: Of the 90 enrolled patients, aged 6.4-17.5 years, 79 (88%) completed the study. Stable daily doses were 32.0 and 32.5 mg for MLR and IR-MPH, respectively. All efficacy parameters were significantly improved from baseline. A total of 73.2% and 81.0% of patients on MLR and IR-MPH were rated as "much" or "very much improved" on the CGI. A total of 77.4% and 81.1% of patients were normalized on the CPRS-R and 78.9 and 90.4% of patients were normalized on the CTRS-R for MLR and IR-MPH, respectively. The mean CASE score was not different from baseline for either treatment.

Efficacy of a novel biphasic controlled-release methylphenidate formula in adults with attention-deficit/hyperactivity disorder: results of a double-blind, placebo-controlled crossover study.

OBJECTIVE: To evaluate the efficacy and safety of a new biphasic multilayer-release (MLR) methylphenidate formulation in a double-blind, placebo-controlled crossover study of adults with attention-deficit/hyperactivity disorder (ADHD). METHOD: Adults 18 to 60 years of age with a DSM-IV diagnosis of ADHD entered a no-medication baseline week and were then randomly assigned to once-daily MLR methylphenidate or matching placebo. Patients were titrated to optimal effect over 1 to 3 weeks followed by 2 weeks of treatment on a stable dose. The same titration protocol was repeated with the alternate treatment. Clinical Global Impressions scale (CGI) and Conners' Adult ADHD Rating Scales (Self-rated, CAARS-S, and Observer-rated, CAARS-O) were collected at weekly clinic visits. The study was conducted between October 2003 and April 2004. RESULTS: Fifty patients were randomly assigned to treatment, and 39 were analyzed in a per-protocol population (23 men, 16 women; mean age = 37.9 years). CGI-Improvement scores of subjects taking MLR methylphenidate were significantly improved compared with placebo (Global Improvement: 2.6 vs. 3.7; p = .0015). MLR methylphenidate produced improvements over placebo on the ADHD Index T scores of the CAARS-S (12.2 vs. 5.4 [change from baseline score]; p = .0083) and the CAARS-O (10.9 vs. 6.6 [change from baseline score]; p = .1404). The most frequent adverse events for MLR methylphenidate and placebo were headache (26% and 24%, respectively), anorexia (22% and 6%), insomnia (22% and 8%), nervousness (20% and 4%), and nausea (16% and 8%). There were no serious adverse events. CONCLUSIONS: Once-daily MLR methylphenidate produces significant improvements in ADHD symptoms and situational behavior in adult patients with ADHD, with a prolonged duration of effect and minimal side effects, thus having the potential to improve compliance and, therefore, treatment outcomes in routine clinical use.

Single-dose pharmacokinetics of multilayer-release methylphenidate and immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

The objective of this study was to compare the single-dose pharmacokinetics of multilayer-release and immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder. Patients 6- to 12-years-old with a DSM-IV diagnosis of attention-deficit/hyperactivity disorder were randomized to receive multilayer-release methylphenidate (qd) or immediate-release methylphenidate (bid) at equivalent doses, with a 14-day washout between treatments. Plasma samples were collected predosing and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdose. Pharmacokinetic analysis was conducted on 14 patients (1 female, 13 male; mean age: 9.6 +/- 2.5 years [range, 6-12]). The mean dose of methylphenidate received by these patients in both phases of the study was 38.6 mg/d (range, 20-80 mg/d). The relative AUC(0-t) and C(max 0-4) ratios for multilayer-release compared with immediate-release methylphenidate were 100.8% and 78.8%, respectively. Multilayer-release methylphenidate produces a biphasic concentration-time profile, with a rapid initial increase in plasma concentration that is maintained throughout the school day.

Pharmacokinetics and pharmacodynamics of once-daily controlled-release oxybutynin and immediate-release oxybutynin.

Oxybutynin is used to treat patients with urinary urgency, frequency, and urge incontinence. In this 2-way, multiple-dose, crossover study, the pharmacokinetics and pharmacodynamics of once-daily controlled-release oxybutynin were compared with immediate-release oxybutynin. Eighteen healthy male volunteers received one 15-mg controlled-release oxybutynin tablet once daily for 5 days or one 5-mg immediate-release oxybutynin tablet every 8 hours for 5 days. The washout period between treatments was > or =7 days. The mean steady-state AUC for oxybutynin following controlled-release oxybutynin treatment was higher (73.0 ng.h/mL) than following immediate-release oxybutynin treatment (53.6 ng.h/mL) (P = .0001). The mean C(max) was lower for controlled-release oxybutynin (5.7 ng/mL) than for immediate-release oxybutynin (7.5 ng/mL) (P = .0051), with a smaller fluctuation in oxybutynin plasma concentration for controlled-release oxybutynin (135.6%) than for immediate-release oxybutynin (319.3%) (P = .0001). Mean stimulated saliva output was greater for controlled-release oxybutynin, and mean dry mouth severity was less than immediate-release oxybutynin.

A double-blind randomized dose-response study comparing daily doses of 5, 10 and 15 mg controlled-release oxybutynin: balancing efficacy with severity of dry mouth.

OBJECTIVE: To assess the efficacy, incidence of dry mouth and overall satisfaction with initial doses of 5, 10 and 15 mg of a new, once-daily, controlled-release (CR) form of oxybutynin for treating urge urinary incontinence (UUI). PATIENTS AND METHODS: Patients who reported urinary incontinence (UI) (one or more episodes/diary) and voiding frequency (eight or more voids/day) or urgency (one or more episodes/diary) during a 2-week baseline were randomized to once-daily 5, 10 or 15 mg CR oxybutynin for 4 weeks. Daily episodes of UI, voids, urgency, adverse events, dry mouth and satisfaction were recorded in a 3-day diary at baseline and after 4 weeks of treatment. In all, 237 patients were randomized and evaluated. RESULTS: Episodes of UI, voids and urgency were significantly reduced over the study period at all doses. Daily UI episodes were significantly lower with 15 mg/day than 5 and 10 mg/day. Dry mouth symptoms were similar in the 10 and 15 mg/day groups, and higher than in the 5 mg/day group. However, significantly greater overall satisfaction was reported with 15 than 5 mg/day. CONCLUSIONS: There were significant dose-response relationships with CR oxybutynin for both UI episodes and dry mouth. The greatest satisfaction was with 15 mg/day, and the severity of dry mouth was comparable at 10 mg/day, indicating that greater efficacy at the higher dose did not compromise tolerability.

Efficacy and safety of controlled-release oxycodone and standard therapies for postoperative pain after knee or hip replacement.

BACKGROUND: Standard therapy (ST) for postoperative pain after knee and hip replacement at the Hamilton Health Sciences Henderson Hospital consists of epidural analgesia or patient-controlled analgesia for the first 48 hours, followed by oral or parenteral analgesics, or both, on an as-needed basis. We compared the efficacy and safety of scheduled controlled-release (CR) oxycodone hydrochloride (OxyContin; Purdue Pharma, Pickering, Ont.) and ST for postoperative pain 48 hours after primary knee and hip replacement. METHODS: In 2 separate 3-week studies of similar design, pain intensity, pain relief, length of hospital stay, analgesic use and side effects of CR oxycodone (n = 70) and ST (n = 101) were evaluated. In the CR oxycodone trial, a dose de-escalation protocol was used. RESULTS: At the time of discharge from hospital, patients in the CR oxycodone group recorded lower mean (and standard deviation) pain intensity scores than the ST group (20.2 [17.9] v. 27.7 [21.5] mm on a 100-mm visual analogue scale; p = 0.021). Length of hospital stay was 5.5 and 6.4 days for the CR oxycodone and ST groups respectively (p < 0.001). CR oxycodone patients used less opioid (morphine equivalent) while in hospital than ST patients (p < 0.001), and the average number of daily administrations of analgesics in hospital was 2.1 and 3.5 for CR oxycodone and ST patients respectively (p < 0.001). ST patients reported more nausea and vomiting, pruritus and fever than the CR oxycodone patients, but less somnolence, constipation, dizziness, confusion and tachycardia. CONCLUSIONS: CR oxycodone every 12 hours is as effective as ST in treating postoperative pain but length of hospital stay was shorter and analgesic administration in the hospital was used less frequently, providing potential hospital cost savings and reduced use of health care resources.

A randomized, double-blind, parallel-group comparison of controlled- and immediate-release oxybutynin chloride in urge urinary incontinence.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of a new PO controlled-release (CR) QD oxybutynin tablet relative to PO immediate-release (IR) TID oxybutynin in patients with urge urinary incontinence (UI). METHODS: In this multicenter, double-blind trial, patients with UI (> or = 7 episode/wk) and frequency (> or = 8 micturitions/d) were randomized to CR or IR oxybutynin for 6 weeks. Patients initiated treatment at 15 mg/d and the dose was adjusted (in 5-mg/d increments) over 2 weeks according to tolerability. Efficacy (UI episodes, voids, absorbent pads used, urgency, and volume voided per micturition) was assessed during the final 2 weeks of treatment. Tolerability was assessed by evaluating adverse events and treatment withdrawals. RESULTS: Of the 125 patients randomized, 94 (75%) were evaluable for efficacy; tolerability was assessed in all patients. In the CR group, 48 patients (91%) were women and 5 (9%) were men; the mean (SD) age was 58.0 (12.4) years (range, 26-78 years). In the IR group, 37 patients (90%) were women and 4 (10%) were men; the mean (SD) age was 60.6 (14.8) years (range, 26-83 years). Both CR and IR oxybutynin significantly reduced the mean number of total UI episodes per week (both P < 0.001 vs baseline). Both treatments produced equivalent reductions in mean voiding frequency and urinary urgency (all P < 0.001 vs. baseline). Significantly more patients rated CR oxybutynin tolerable on the initial dose of 15 mg/d (P = 0.020) and completed the study at a dose of > or = 15 mg/d (P = 0.018). Dry mouth was the most common adverse event, reported by 68% and 72% of patients in the CR and IR oxybutynin groups, respectively. CONCLUSIONS: Among the patients with urge UI included in this study, CR oxybutynin was as effective as IR oxybutynin for improving primary symptoms, with the additional benefit of QD administration.

Preliminary evaluation of a new controlled-release oxybutynin in urinary incontinence.

OBJECTIVE: To conduct a preliminary evaluation of a new oral formulation of controlled-release (CR) oxybutynin tablet taken once-daily in patients with urinary urge incontinence. RESEARCH DESIGN AND METHODS: A single-centre, open-label, 8-week study was conducted. Patients with urodynamically-confirmed detrusor instability, micturition frequency (>/= 8 voids/day) and/or urinary incontinence (>/= 2 incontinence periods/day) were enrolled. The study duration was 8 weeks: patients received IR oxybutynin (2.5-5 mg bid) for 2 weeks, followed by a 2-week washout/baseline period to avoid carryover effects, and oral CR oxybutynin (15 mg OD) for 4 weeks. Daily void frequency, fluid intake, urinary incontinence episodes, and spontaneously reported adverse events were recorded in a daily diary for five consecutive days in each treatment period. RESULTS: Of 12 enrolled patients, 9 patients efficacy; all patients were evaluable for safety. completed the study and were evaluable for Compared to baseline/washout, CR oxybutynin reduced UI episodes/day by 45% (p = 0.13) and micturitions/day by 15% (p = 0.07). Treatment with IR oxybutynin (mean dose: 6.7 +/- 2.5 mg/day) reduced UI episodes/day from baseline by 7% (p = 0.58) and voids/day by 6% (p = 0.29). Fluid intake remained consistent at approximately 2 litres/day during all study periods. The most common adverse event was dry mouth. CONCLUSIONS: Based on the reductions in daily frequency of incontinence and micturition following 4-weeks treatment, CR oxybutynin (15 mg OD) was at least as effective as the patients' previous dose of IR oxybutynin (mean dose: 6.7 +/- 2.5 mg/day). These improvements were achieved without restriction of fluid intake. Initial 15 mg doses of CR oxybutynin appear to be well tolerated.