Extended-release Immediate-release Research Articles

A Cross-Sectional Study of Tampering in Xtampza ER, an Abuse-Deterrent Formulation of an Extended-Release Opioid, in a Treatment Center Population.

While the current landscape of opioid use disorder (OUD) is complicated by the increase in use of non-prescription opioids, prescription opioids continue to be frequently used in non-medical ways. In response to this abuse, pharmaceutical companies have developed abuse deterrent formulations (ADFs) for extended-release (ER) opioids. To test the effectiveness of Xtampza ER ADF (oxycodone myristate) at reducing tampering, its rate of tampering in a treatment-center population was compared to immediate release (IR) single entity (SE) oxycodone, other ER oxycodone opioids, and ER oxymorphone. Data were collected between the third quarter of 2018 and the third quarter of 2021 from individuals entering nationally distributed opioid treatment programs. To determine odds of tampering with Xtampza ER compared to each comparator, a logistic model was fit with a random intercept allowing for multiple drugs in each subject. Within-subject correlation was assumed to have a compound symmetric relationship. Overlap among the categories of drug tampering was high. Logistic regression analyses found that oxycodone myristate had lower odds of tampering when compared to both IR SE oxycodone (OR = 0.23 [95% CI0.11, 0.50], p = 0.0002) and ER oxymorphone (OR = 0.30 [95% CI0.14, 0.67], p = 0.0038). Oxycodone myristate was not significantly different from other ER oxycodone opioids (OR = 0.5 [95% CI0.24, 1.03], p = 0.0612). These findings did not change when the estimates were adjusted for age and sex. Drugs employing ADF technology may reduce the likelihood of tampering when compared to non-ADF formulations in a treatment-center population, which represents an opportunity for intervention in OUD among those still requiring pain management.

Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies

BackgroundImmediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing. ObjectiveReport individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID. MethodsPD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale. ResultsOverall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were −5.5 [−9.8, −1.2], p = 0.012 and −5.2 [−9.5, −0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively). ConclusionsIR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

Bioavailability and Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets in Healthy Volunteers: Results from Three Randomized, Crossover, Open-Label, Phase 1 Studies.

IntroductionIn February 2018, OS320—an amantadine extended-release (ER) tablet formulation with once-daily morning administration—was approved for the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions in adults. The purpose of this study was to describe three phase 1 studies that assessed the pharmacokinetics (PK) and bioavailability of amantadine ER in healthy adult volunteers.MethodsStudy 1 was an open-label, four-treatment, single-dose, crossover study comparing amantadine ER 129, 193, and 258 mg tablets with an equivalent dose of immediate-release (IR) amantadine 40 mg/5 mL syrup. Study 2 was an open-label, single-dose, crossover food-effect study with amantadine ER 258 mg. Study 3 was an open-label, multiple-dose, crossover study comparing amantadine ER and amantadine IR syrup.ResultsAmantadine ER displayed a steady release of amantadine, with the peak amantadine concentration occurring at ~ 7.5 h postdose or in the middle of the day (following a morning dose) with steady-state administration. Administration of amantadine ER 258 mg with a high-fat meal did not affect amantadine bioavailability. Amantadine plasma exposure increased proportionally with increasing doses, and at steady state, amantadine exposure from an amantadine ER 258-mg tablet was bioequivalent to twice-daily 129-mg amantadine IR syrup.ConclusionThe PK profile of amantadine ER 129-mg, 193-mg, and 258-mg tablets allows for once-daily dosing in the morning; the 24-h average amantadine plasma concentration is equivalent to that for the same daily dose of IR amantadine administered twice daily.FundingOsmotica Pharmaceutical US LLC.

Evaluation of real-world persistence of propiverine and trospium chloride in treatment of overactive bladder in Germany.

Treatment persistence poses a crucial criterion for therapeutic success. Like in many other chronic diseases, in overactive bladder (OAB) syndrome also, many patients discontinue their treatment for diverse reasons. In order to evaluate the persistence in medication, this paper presents data of propiverine extended release (ER) and trospium chloride immediate release (IR) for three consecutive quarters, thus giving an insight into the probability of treatment discontinuation for these two drugs. Prescription data from German health insurances were analyzed. The frequency of follow-up prescriptions and drop-outs for propiverine ER and trospium chloride IR were compared for treatment-naïve, restarted, and switched patients after treatment initiation (quarter 1) for a period of 9 months (three consecutive calendar quarters). In all analyzed quarters, the percentage of follow-up prescriptions was significantly higher for propiverine ER than for trospium chloride IR. The chance of a follow-up prescription was also significantly higher for propiverine ER than for trospium chloride IR, although, in general, both drugs showed a decrease of follow-up prescriptions over time. This comparison of propiverine ER (once-daily administration) and trospium chloride IR (in a multiple dose administration) in patients with OAB syndrome demonstrates that there are substantial differences in the odds of a follow-up prescription. The longer a patient adheres to a therapeutic treatment plan, the better the chances for improvement of symptoms and having a positive impact on activities of daily living.

Challenging obesity, diabetes, and addiction: the potential of lorcaserin extended release.

Obesity is a global epidemic that is a leading cause of preventable death. In addition to lifestyle modification, there are numerous obesity treatments for clinicians to consider, including medications. Lorcaserin immediate release/extended release (IR/XR) is a US Food and Drug Administration approved medication for overweight and obese patients to be used with lifestyle modifications. Lorcaserin is thought to reduce weight by targeting the serotonin (5HT2c) system to induce satiety. Lorcaserin IR has been shown to be effective in reducing weight in overweight (body mass index [BMI] > 27 kg/m2) and obese (BMI > 30 kg/m2) participants in three large Phase III trials. In addition, lorcaserin has been shown to reduce post-cessation weight gain and improved smoking cessation in a randomized placebo-controlled trial. A recent meta-analysis suggested in overweight diabetic patients lorcaserin may be added to first-line oral hypoglycemic medications to enhance reduction in glycated hemoglobin. Lorcaserin is generally well tolerated with the most common side effect being headache, which is typically self-limiting. Lorcaserin XR (once daily) was recently approved and has been shown to be bioequivalent to lorcaserin IR (twice daily) in a pivotal study. Lorcaserin XRs, main advantage over the IR formulation is the once daily dosing regimen, which likely would lead to improved adherence and thus improved clinical effectiveness. The present review will evaluate the lorcaserin clinical studies (obesity, diabetes, and addiction), XR bioequivalence studies, pharmacogenomics of the serotonin (5HT2c) system, and adherence data in once daily versus twice daily medications.

Prevalence of nonmedical use and routes of administration for prescription stimulant medications among adults in a substance abuse treatment population

The aim was to examine prevalence of past 30-day prescription stimulant nonmedical use (NMU) by adults assessed for substance use problems and to better understand patterns of route of administration (ROA) and drug problem severity. Data were collected from a computer administered assessment of substance use problems completed by adults (age ≥ 18) using the Addiction Severity Index-Multimedia Version (ASI-MV®) as part of the clinical intake process between January 2013 and March 2016. A cross-sectional observational study examined prevalence and prescription-adjusted prevalence of past 30-day NMU of prescription stimulants and compound-specific use by ROA (oral, snort, smoke, inject, other oral, and alternate ROA). Compounds of interest were amphetamine extended-release (ER), amphetamine immediate-release (IR), amphetamine mixed salts, methylphenidate ER, and methylphenidate IR. Of 198,411 respondents, 4,185 reported prescription stimulant NMU, prevalence ranged from 0.33% for methylphenidate IR to 1.61% for amphetamine mixed salts. Prescription-adjusted prevalence of NMU was highest for methylphenidate IR (0.51%) and lowest for amphetamine ER (0.28%). The most common ROA was oral, swallowed whole followed by snorting. There was a greater probability of nonmedical prescription stimulant use among respondents with higher drug severity ratings. Results suggest that one should not overlook the impact of prescription stimulant NMU in adults in treatment for substance use problems. NMU of prescription stimulants was associated with riskier routes of administration than reported for college student samples. A pattern of high-risk alternate ROA and increasing drug problem severity has important implications of substance use evaluation.

The ALERRT® instrument: a quantitative measure of the effort required to compromise prescription opioid abuse-deterrent tablets

ABSTRACTBackground: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT® instrument (PinneyAssociates; Bethesda, MD) uses visual analog scales to assess the labor, effort, and resources necessary to physically compromise AD product candidates in standardized settings. Objective: Use the ALERRT® instrument for testing morphine abuse-deterrent, extended-release, injection-molded tablets (ADER-IMT) 60 and 100 mg and the comparators immediate-release (IR) morphine sulfate 30 mg and extended-release (ER) morphine sulfate 60 mg. Methods: Four technicians tested the products using 10 household tools. The ALERRT instrument quantified effort (all tools) and time (3 preselected tools) required for manipulation. Results: Morphine-ADER-IMT 60 and 100 mg were difficult to manipulate, as demonstrated by high scores (mean range, 71.0−99.0 and 77.0−99.5, respectively). IR and ER morphine sulfate were easy to manipulate (low scores; mean range, 2.0−14.8 and 2.3−17.5, respectively). Statistically significant mean differences between morphine-ADER-IMT and comparators’ ALERRT scores were observed. Manipulations of morphine-ADER-IMT 60 and 100 mg for 300 seconds failed to produce substantial powdering. Manipulations of IR morphine sulfate (mean range, 65.5−175.8 seconds) and ER morphine sulfate (49.3−163.0 seconds) produced substantial to complete powdering in 92% of tablets. Conclusions: Morphine-ADER-IMT was extremely difficult to manipulate versus non-AD formulations of morphine. The ALERRT system differentiated the degree of effort for manipulation of morphine-ADER-IMT and non-AD morphine formulations, indicating sensitivity of this instrument as part of Category 1 testing. By measuring the degree of effort required for manipulation, the ALERRT instrument provides an empirical assessment into the relative difficulty of manipulating opioid analgesics for abuse.

Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR).Design. Randomized, double-blind, placebo-controlled, crossover study.Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users.Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was “at the moment” drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety.Results. Mean maximum effect (Emax) for “at the moment” drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective “at the moment” drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%).Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated.

Efficacy of single-dose, extended-release naproxen sodium 660 mg in postsurgical dental pain: two double-blind, randomized, placebo-controlled trials

Objective:To evaluate the efficacy of a novel formulation of extended-release/immediate-release (ER) naproxen sodium over 24 h in a dental pain model.Research design and methods:Two randomized, double-blind, placebo-controlled trials in moderate to severe pain after extraction of one or two impacted third molars (at least one partial mandibular bony impaction). Treatment comprised oral ER naproxen sodium 660 mg (single dose), placebo (both studies) or immediate-release (IR) naproxen sodium 220 mg tid (study 2).Main outcome measures:Primary efficacy endpoint: 24-h summed pain intensity difference (SPID). Secondary variables included total pain relief (TOTPAR), use of rescue medication. All treatment-emergent adverse events were recorded.Clinical trial registration:NCT00720057 (study 1), NCT01389284 (study 2).Results:Primary efficacy analyses: pain intensity was significantly lower over 24 h with ER naproxen sodium vs. placebo (p < 0.001), with significant relief from 15 min (study 2). In study 2, ER naproxen sodium was non-inferior to IR naproxen sodium, reducing pain intensity to a comparable extent over 24 h. TOTPAR was significantly greater with ER and IR naproxen sodium vs. placebo at all time points, with generally comparable differences between active treatments. Significantly more placebo patients required rescue medication vs. ER and IR naproxen sodium from 2–24 h post-dose. Once daily ER naproxen sodium was generally safe and well tolerated, with a similar safety profile to IR naproxen sodium tid.Limitations:The studies were single dose, with limited ability to assess efficacy or safety of multiple doses over time. As the imputed pain score meant that estimated treatment differences may have been biased in favor of ER naproxen sodium, a post hoc analysis evaluated the robustness of the results for pain relief.Conclusions:A single dose of ER naproxen sodium 660 mg significantly reduced moderate to severe dental pain vs. placebo and was comparable to IR naproxen sodium 220 mg tid. Significant pain relief was experienced from 15 min and sustained over 24 h, resulting in a reduced need for rescue medication. ER naproxen sodium 660 mg once daily is a convenient and effective therapy providing 24 h relief of pain.

(401) Analgesic effectiveness of a new, extended-release ibuprofen in postoperative dental pain

Analgesic effects of an immediate-release/extended-release (IR/ER) 600 mg formulation of ibuprofen (IBU) with q12h dosing were evaluated in 2 single-center, randomized, double-blind, placebo-controlled dental pain studies (Study 1: single dose, 24-hour study; Study 2: multiple doses, 48-hour study). Subjects aged 16–40 years with at least moderate pain following third molar extraction received single doses of 2 IBU 600 mg IR/ER formulations (A or B), naproxen sodium (NAP) 220 mg, or placebo (2:2:2:1 ratio) in Study 1; 4 doses IBU 600 mg IR/ER or placebo (1:1 ratio) in Study 2. Primary efficacy: Study 1, time-weighted sum of pain intensity difference (SPID) scores from 0–12 and 8–12 hours; Study 2, time-weighted sum of pain relief and pain intensity differences (SPRID) from 0–12 and 8–12 hours. In Study 1 (N=196), mean (standard deviation [SD]) SPID 0–12 scores were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) and mean (SD) SPID 8–12 scores were -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) for placebo, IBU IR/ER A, IBU IR/ER B, and NAP, respectively (P<0.001, all comparisons vs placebo). In Study 2 (N=106), mean (SD) SPRID 0–12 scores were 18.2 (20.0) vs 41.5 (21.0) and mean (SD) SPRID 8–12 scores were 10.3 (12.0) vs 18.4 (12.1) for placebo and IBU IR/ER, respectively (P<0.001, both favoring IBU IR/ER). SPID score separation from placebo at predefined intervals was maintained throughout the 48-hour study, except for the 20- to 24-hour interval. Significantly more AEs occurred with placebo in Study 1 (P=0.045) and Study 2 (P=0.001); gastrointestinal AEs predominated in subjects receiving placebo, likely due to opioid rescue medication use. No serious AEs occurred. IBU 600 mg IR/ER administered every 12 hours provided safe and effective analgesia following both single and multiple doses. Supported by Pfizer Consumer Healthcare. Analgesic effects of an immediate-release/extended-release (IR/ER) 600 mg formulation of ibuprofen (IBU) with q12h dosing were evaluated in 2 single-center, randomized, double-blind, placebo-controlled dental pain studies (Study 1: single dose, 24-hour study; Study 2: multiple doses, 48-hour study). Subjects aged 16–40 years with at least moderate pain following third molar extraction received single doses of 2 IBU 600 mg IR/ER formulations (A or B), naproxen sodium (NAP) 220 mg, or placebo (2:2:2:1 ratio) in Study 1; 4 doses IBU 600 mg IR/ER or placebo (1:1 ratio) in Study 2. Primary efficacy: Study 1, time-weighted sum of pain intensity difference (SPID) scores from 0–12 and 8–12 hours; Study 2, time-weighted sum of pain relief and pain intensity differences (SPRID) from 0–12 and 8–12 hours. In Study 1 (N=196), mean (standard deviation [SD]) SPID 0–12 scores were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) and mean (SD) SPID 8–12 scores were -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) for placebo, IBU IR/ER A, IBU IR/ER B, and NAP, respectively (P<0.001, all comparisons vs placebo). In Study 2 (N=106), mean (SD) SPRID 0–12 scores were 18.2 (20.0) vs 41.5 (21.0) and mean (SD) SPRID 8–12 scores were 10.3 (12.0) vs 18.4 (12.1) for placebo and IBU IR/ER, respectively (P<0.001, both favoring IBU IR/ER). SPID score separation from placebo at predefined intervals was maintained throughout the 48-hour study, except for the 20- to 24-hour interval. Significantly more AEs occurred with placebo in Study 1 (P=0.045) and Study 2 (P=0.001); gastrointestinal AEs predominated in subjects receiving placebo, likely due to opioid rescue medication use. No serious AEs occurred. IBU 600 mg IR/ER administered every 12 hours provided safe and effective analgesia following both single and multiple doses. Supported by Pfizer Consumer Healthcare.

Comparative steady-state pharmacokinetic study of an extended-release formulation of itopride and its immediate-release reference formulation in healthy volunteers

BackgroundThis study was conducted to compare the oral bioavailability of an itopride extended-release (ER) formulation with that of the reference immediate-release (IR) formulation in the fasting state. The effect of food on the bioavailability of itopride ER was also assessed.MethodsA single-center, open-label, randomized, multiple-dose, three-treatment, three-sequence, crossover study was performed in 24 healthy male subjects, aged 22–48 years, who randomly received one of the following treatments for 4 days in each period: itopride 150 mg ER once daily under fasting or fed conditions, or itopride 50 mg IR three times daily in the fasting state. Steady-state pharmacokinetic parameters of itopride, including peak plasma concentration (Cmax) and area under the plasma concentration versus time curve over 24 hours after dosing (AUC0–24h), were determined by noncompartmental analysis. The geometric mean ratio of the pharmacokinetic parameters was derived using an analysis of variance model.ResultsA total of 24 healthy Korean subjects participated, 23 of whom completed the study. The geometric mean ratio and its 90% confidence interval of once-daily ER itopride versus IR itopride three times a day for AUC0–24h were contained within the conventional bioequivalence range of 0.80–1.25 (0.94 [0.88–1.01]), although Cmax was reached more slowly and was lower for itopride ER than for the IR formulation. Food delayed the time taken to reach Cmax for itopride ER, but AUC0–24h was not affected. There were no serious adverse events and both formulations were generally well tolerated.ConclusionAt steady state, once-daily itopride ER at 150 mg has a bioavailability comparable with that of itopride IR at 50 mg given three times a day under fasting conditions. Food delayed the absorption of itopride ER, with no marked change in its oral bioavailability.

Patient considerations in the use of tapentadol for moderate to severe pain

Poorly controlled acute and chronic pain can increase morbidity, impair quality of life and prolong disability. Over 80 percent of post surgical patients report moderate to severe uncontrolled postoperative pain. Over-reliance on potent opioid agonists can lead to several opioid related side effects such as gastrointestinal intolerability, respiratory depression and cognitive impairment. A recently approved dual acting central analgesic tapentadol may offer improved tolerability over traditional opioid agonists while having multimodal opioid and nonopioid analgesic benefits. Tapentadol, classified by the US Food and Drug Administration as a class 2 opioid, is currently marketed in the United States as immediate release (IR) NUCYNTA® for moderate to severe acute pain in tablets of 50 mg, 75 mg, and 100 mg, and as extended release (ER) NUCYNTA ER® for the treatment of chronic moderate to severe pain in tablets of 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg. Tapentadol is a low affinity mu opioid receptor agonist and a norepinephrine reuptake inhibitor. Tapentadol has no active metabolites and this property makes it useful in patients with hepatic and renal failure. Clinical trials with tapentadol IR showed that there was improved gastrointestinal tolerability and similar pain relief as compared to oxycodone IR. Tapentadol ER allows for twice daily dosing. Clinical trials showed that tapentadol ER could effectively relieve moderate to severe chronic pain and was associated with significantly fewer gastrointestinal adverse effects as compared to oxycodone controlled release. Tapentadol ER is indicated and has Food and Drug Administration approval for the treatment of chronic painful diabetic neuropathy. The most common side effects of tapentadol are nausea (30%), vomiting (18%), dizziness (24%), and somnolence (15%). Tapentadol, due to its potential synergistic effects on norepinephrine levels, is contraindicated in patients who have taken monoamine oxidase inhibitors within the last 14 days. Caution has to be exercised with the use of tapentadol IR and tapentadol ER in the presence of other central nervous system depressants such as neuroleptics, opioids, illicit drugs, muscle relaxants, sedatives, and anxiolytics.

Cost-effectiveness analysis of anti-muscarinic agents for the treatment of overactive bladder

Objective:To determine the cost-effectiveness of pharmacologic treatments for overactive bladder (OAB) in the US.Methods:A decision model was constructed based on studies of effectiveness, adverse consequences, co-morbid conditions, and medical costs for the treatment of OAB. Treatment success was defined as no incontinence episodes for 3–7 days or 3–7 consecutive dry days. Estimates of treatment success were obtained from clinical trials and included darifenacin, fesoterodine, oxybutynin immediate release (IR), oxybutynin extended release (ER), oxybutynin topical gel, oxybutynin transdermal patch, solifenacin, tolterodine IR, tolterodine ER, trospium IR, and trospium ER. Probabilistic sensitivity analysis was conducted using Monte Carlo simulation.Results:A total of 51 OAB studies were identified and 11 reported treatment success. Mean continence rates varied in the literature from 21.0% with trospium IR to 51.0% with solifenacin. The 95% CI for solifenacin's success rate was statistically higher than other regimens due to the higher continence rates from the clinical trials. Oxybutynin IR and oxybutynin ER were significantly less costly than other products. The product with the lowest incremental cost-effectiveness ratio (ICER) relative to oxybutynin IR was solifenacin at $1338 (±168) per additional continent patient. The cost-effectiveness acceptability curve indicated that oxybutynin IR was the most cost-effective regimen when willingness-to-pay values were less than $10,000 per additional continent patient. Solifenacin was most cost-effective at higher willingness-to-pay values.Conclusion:There was broad overlap in effectiveness among the anti-muscarinic products, except solifenacin had a significantly higher continence rate. Oxybutynin IR and oxybutynin ER were significantly less costly than other anti-muscarinic regimens, and these two products have a useful role to play in the management of OAB. However, for patients unable to tolerate the lower cost products, formularies benefit from solifenacin among branded products since the cost-effectiveness acceptability curve demonstrated it was the product most likely to be cost-effective after oxybutynin IR.

Efficacy and Safety of Extended- Versus Immediate-Release Pramipexole in Japanese Patients With Advanced and L-dopa–Undertreated Parkinson Disease

To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Dose Equivalence of Immediate-Release Hydromorphone and Once-Daily Osmotic-Controlled Extended-Release Hydromorphone: A Randomized, Double-Blind Trial Incorporating a Measure of Assay Sensitivity

Dose selection of a once-daily, osmotic-controlled extended-release (ER) hydromorphone assumes that this drug and immediate-release (IR) hydromorphone are dose equivalent. This trial evaluated dose equivalence using a measure of assay sensitivity. Patients were converted to open-label IR hydromorphone, underwent dose titration, and those on a satisfactory dose entered a randomized, double-blind phase receiving 7 days of: 1) hydromorphone IR 5 times/day at approximately this dose; 2) once-daily hydromorphone ER at this dose; or 3) once-daily hydromorphone ER at one-half this dose. Efficacy was measured using breakthrough medication use, pain, sleep, and global assessments. Of 148 patients, 113 (76%) were randomized. IR and full-dose ER groups produced comparable effects on all measures. Although the prespecified primary analysis of the difference in total daily dose of breakthrough medication between the full-dose ER and half-dose ER groups was not significant, more patients in the half-dose ER group required an increase in breakthrough medication (P = .026) and the half-dose ER group both increased the number of breakthrough doses (P = .026) and had greater percent change in the total daily dose of breakthrough medication (P = .037) than the full-dose group, suggesting that switching from IR to ER hydromorphone at the same daily dose provides equivalent analgesia. PerspectiveIn a randomized, double-blind trial, the same total daily dose of immediate-release hydromorphone and once-daily osmotic-controlled extended-release hydromorphone had comparable effects. Detection of different effects between blinded dose levels was used as a measure of assay sensitivity. The measure of assay sensitivity can enhance the interpretation of dose equivalence or noninferiority trials.

Comparative adherence to oxybutynin or tolterodine among older patients

Dear Editor,In their short communication, Gomes et al. [1] provide inter-esting data on the real-life use of two antimuscarinic agentsused in urinary incontinence. Nonetheless, in many countriesaround the world, these two agents are available in a range offormulations, as oxybutynin immediate-release (IR) tablets,extendedrelease(ER)tablets,andtransdermalpatches;andastolterodine IR tablets and ER capsules. Numerous studiessuggest that the incidence of dry mouth, cited by patients asa common reason for treatment discontinuation, varies signif-icantly between these formulations [2–4]. Consequently, theclinical value of the report by Gomes et al. would be greatlyincreased if the profile of oxybutynin and tolterodine formu-lations that comprise their data was described.Yours sincerely,Angus ThompsonReferences

Extended-release pramipexole in early Parkinson disease

To assess the clinical efficacy of a novel once-daily extended-release (ER) formulation of the dopamine agonist pramipexole as monotherapy in patients with early Parkinson disease (PD) and establish its noninferiority vs standard immediate-release (IR) pramipexole. This was a multicenter, double-blind, parallel study of patients with early PD not receiving levodopa or dopamine agonists, randomly assigned to pramipexole IR, pramipexole ER, or placebo. Seven-week flexible titration was followed by 26-week maintenance, with levodopa permitted as rescue medication. The primary analysis was to test pramipexole ER noninferiority to pramipexole IR based on a change in the Unified Parkinson's Disease Rating Scale (UPDRS) part II+III score at 33 weeks, with noninferiority predefined as a treatment group difference for which the lower bound of the 95% confidence interval (CI) did not exceed -3 points. Among 213 ER and 207 IR recipients, the adjusted mean 33-week UPDRS II+III change (excluding levodopa rescue effects) was -8.2 for ER and -8.7 for IR, a difference of -0.5 with a 95% CI of -2.3 to 1.3. Compared with placebo (n = 103), pramipexole ER and pramipexole IR were significantly superior on UPDRS II+III score, all key secondary outcomes, and almost all other endpoints. On the 39-item Parkinson Disease Questionnaire, superiority of pramipexole ER failed to reach statistical significance. Both formulations were equally safe and well-tolerated. As monotherapy for early PD, pramipexole ER was noninferior to pramipexole IR and significantly more effective than placebo. Tolerability and safety did not differ between the formulations. This study provides Class I evidence that pramipexole ER is not inferior to pramipexole IR in patients with early PD.

Abuse risks and routes of administration of different prescription opioid compounds and formulations

BackgroundEvaluation of tamper resistant formulations (TRFs) and classwide Risk Evaluation and Mitigation Strategies (REMS) for prescription opioid analgesics will require baseline descriptions of abuse patterns of existing opioid analgesics, including the relative risk of abuse of existing prescription opioids and characteristic patterns of abuse by alternate routes of administration (ROAs). This article presents, for one population at high risk for abuse of prescription opioids, the unadjusted relative risk of abuse of hydrocodone, immediate release (IR) and extended release (ER) oxycodone, methadone, IR and ER morphine, hydromorphone, IR and ER fentanyl, IR and ER oxymorphone. How relative risks change when adjusted for prescription volume of the products was examined along with patterns of abuse via ROAs for the products.MethodsUsing data on prescription opioid abuse and ROAs used from 2009 Addiction Severity Index-Multimedia Version (ASI-MV®) Connect assessments of 59,792 patients entering treatment for substance use disorders at 464 treatment facilities in 34 states and prescription volume data from SDI Health LLC, unadjusted and adjusted risk for abuse were estimated using log-binomial regression models. A random effects binary logistic regression model estimated the predicted probabilities of abusing a product by one of five ROAs, intended ROA (i.e., swallowing whole), snorting, injection, chewing, and other.ResultsUnadjusted relative risk of abuse for the 11 compound/formulations determined hydrocodone and IR oxycodone to be most highly abused while IR oxymorphone and IR fentanyl were least often abused. Adjusting for prescription volume suggested hydrocodone and IR oxycodone were least often abused on a prescription-by-prescription basis. Methadone and morphine, especially IR morphine, showed increases in relative risk of abuse. Examination of the data without methadone revealed ER oxycodone as the drug with greatest risk after adjusting for prescription volume. Specific ROA patterns were identified for the compounds/formulations, with morphine and hydromorphone most likely to be injected.ConclusionsUnadjusted risks observed here were consistent with rankings of prescription opioid abuse obtained by others using different populations/methods. Adjusted risk estimates suggest that some, less widely prescribed analgesics are more often abused than prescription volume would predict. The compounds/formulations investigated evidenced unique ROA patterns. Baseline abuse patterns will be important for future evaluations of TRFs and REMS.

Evaluation of the Abuse Potential of Extended Release Hydromorphone Versus Immediate Release Hydromorphone

Immediate release (IR) hydromorphone has experienced significant misuse and abuse. An extended release (ER) hydromorphone formulation has been developed to provide sustained pain relief and may reduce the likelihood for abuse by delaying absorption. In this double-blind, placebo-controlled, randomized, 2-part crossover study, the abuse potential of single oral doses of hydromorphone ER (intact: 16-, 32-, and 64-mg; milled: 8-mg) was compared with 8-mg hydromorphone IR and placebo. After drug administration, subjects with a history of recreational opioid use completed a series of assessments, including subjective effects visual analog scales (eg, drug liking) and Addiction Research Center Inventory With Cole Modification, at several timepoints up to 48 hours postdose. Independent of formulation, maximum at-the-moment drug liking was higher for hydromorphone versus placebo. Maximum drug liking occurred earlier and was higher for 8-mg IR versus 16-mg ER but similar to 32- and 64-mg ER. Most positive effects were lower after 16-mg ER compared with other doses, including 8-mg IR. Bad drug effects were higher for hydromorphone ER, particularly the 64-mg dose. Milled 8-mg ER produced similar subjective effects to 8-mg IR. Comparison of scores after administration of 8-mg IR on 2 separate occasions showed that most assessments exhibited good test-retest reliability, although some scores declined marginally between test and retest. Delayed onset of good drug effects and prominent bad drug effects of hydromorphone ER suggest that, when administered intact, this formulation may have lower abuse potential than hydromorphone IR.

Retrospective evaluation of outcomes in patients with overactive bladder receiving tolterodine versus oxybutynin

The frequency, relative risk, resource utilization, and costs related to comorbidities associated with overactive bladder (OAB) were studied. A retrospective analysis of patients with OAB who initiated treatment with tolterodine extended release (ER), oxybutynin ER, or oxybutynin immediate release (IR) between January 2001 and December 2002 was conducted to evaluate the frequency, relative risk, resource utilization, and costs related to three specific comorbidities associated with OAB: urinary tract infections (UTIs), depression, and fracture. Two patient cohorts (tolterodine ER versus oxybutynin ER and tolterodine ER versus oxybutynin IR) were matched on a 1:1 basis according to their propensity to receive a prescription for tolterodine ER. The frequency and relative risk of UTIs were significantly lower in the tolterodine ER group than in the oxybutynin ER and oxybutynin IR groups. The relative risk of depression was also lower in the tolterodine ER group than the oxybutynin ER and oxybutynin IR groups; however, the differences were only significant in the tolterodine ER versus oxybutynin IR comparison. The utilization of UTI- and depression-related services and the number of antiinfective and antidepressant prescriptions were significantly lower in the tolterodine ER group than in the oxybutynin ER group. UTI- and depression-related costs were generally lower in the tolterodine ER group than in the oxybutynin ER or oxybutynin IR group. Treatment of OAB patients with tolterodine ER was associated with reduced frequency, relative risk, medical and pharmacy resource utilization, and incurred costs related to selected OAB-associated comorbidities compared with treatment with oxybutynin ER or oxybutynin IR.