Ellie He

12-Month safety and effectiveness of once-daily hydrocodone tablets formulated with abuse-deterrent properties in patients with moderate to severe chronic pain.

OBJECTIVE To characterize the long-term safety and effectiveness of Hysingla™ ER, single-entity, once-daily, extended-release hydrocodone bitartrate tablets formulated with abuse-deterrent properties (HYD), offering a new treatment option for appropriate patients with chronic pain. DESIGN An open-label study with a dose-titration period (up to 45 days) and a maintenance period (12 months). PATIENTS, PARTICIPANTS A total of 922 patients with chronic nonmalignant and non-neuropathic moderate to severe pain received open-label HYD tablets 20-120 mg; 728 of these achieved a stabilized dose of HYD at the end of dose-titration and entered the maintenance period. RESULTS The safety profile was similar to that of other oral opioid analgesics, without new or unexpected safety concerns. The most frequent treatment-emergent adverse events (AEs; ≥ 5 percent) were those commonly associated with the use of systemic µ-opioid analgesics, including nausea, constipation, vomiting, fatigue, dizziness, somnolence, and headache. There were 77 (8 percent) patients with a total of 109 nonfatal treatment-emergent serious AEs. Few patients discontinued due to lack of therapeutic effect overall (6 percent), especially during the 12-month maintenance period (4 percent). Pain relief, sleep, functional health, and activities of daily living all improved at the end of the dose-titration period with HYD. These improvements were maintained through the 12-month maintenance period with stable HYD doses and without increase in concomitant supplemental analgesic medications. CONCLUSIONS This long-term study demonstrated the safety and long-term maintenance of analgesic effect of HYD without continued need for dose increase.

A multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of single-entity, once-daily hydrocodone tablets in patients with uncontrolled moderate to severe chronic low back pain

Objectives: This multicenter, randomized, double-blind, placebo-controlled study with an enriched enrollment, randomized withdrawal design was conducted to evaluate the analgesic efficacy and safety of single-entity, once-daily hydrocodone 20 to 120 mg tablets (HYD) in opioid-naive and opioid-experienced patients with uncontrolled moderate to severe chronic low back pain (CLBP). Research design and methods: The primary endpoint was week 12 pain intensity scores (11-point scale, 0 = no pain) using a mixed effect model with repeated measures incorporating a pattern mixture model framework. Responder analysis was a secondary endpoint. Safety was assessed. Results: Out of 905 patients who were treated with HYD during the open-label titration period, 588 (65%) were randomized to continue to receive HYD (n = 296, 20 – 120 mg taken once daily, average daily dose 57 mg) or a matching placebo (n = 292). HYD demonstrated superior pain reduction (p = 0.0016); this result was supported by sensitivity analyses using different approaches to handling missing data. Proportions of patients achieving ≥ 30 and ≥ 50% improvement in pain from screening to week 12 also favored HYD (p = 0.0033 and 0.0225, respectively). HYD was generally well tolerated. Conclusions: HYD was shown to be an efficacious treatment for CLBP in this study. There were no new or unexpected safety concerns detected.

Pain intensity and interference with functioning and well-being in subgroups of patients with chronic pain treated with once-daily hydrocodone tablets

BACKGROUND A previous 52-week trial of patients with chronic noncancer, non-neuropathic pain (CNNP) showed clinically meaningful improvement in pain intensity, pain interference, and physical health-related quality of life (HRQL) following daily treatment with an extended-release, once-daily hydrocodone (Hysingla(®) ER; HYD) bitartrate tablet. OBJECTIVE To examine treatment response within patient subgroups and to assess between-subgroup differences in effectiveness and side effect profile. METHODS Data were from an open-label 52-week trial of treatment with HYD tablets (20-120 mg, once-daily) for patients with moderate-to-severe CNNP. Binary subgroups were defined for the following six factors: age, gender, opioid experience, baseline pain severity, history of depression, and stable HYD dose at completion of a 45-day dose-titration period. Univariable and multivariable models examined changes in average pain intensity (API; 11-point numeric rating scale), pain interference (Brief Pain Inventory-Interference subscale [BPI-I]), physical and mental HRQL (36-item Short Form health survey Physical and Mental Component Summaries [PCS and MCS]), and sleep quality (Medical Outcomes Study Sleep Scale Sleep Problems Index [SPI]) from baseline to maintenance, and subgroup differences in adverse events. RESULTS All subgroups showed clinically meaningful improvements in API, BPII, and PCS scores; no subgroups showed improvements in MCS or SPI. Between subgroup comparisons found greater improvements for opioid-naïve patients and for patients with severe baseline pain. Incidence of adverse events differed minimally between subgroups. CONCLUSION Regardless of subgroup, patients with CNNP treated with HYD showed clinically meaningful improvements in pain intensity, pain interference, and physical HRQL, although not in mental HRQL or sleep quality. Improvements were generally larger for opioid-naïve patients and patients with severe baseline pain.

Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain

Abstract Background: Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla™ ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post-hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23–31% of the study populations). Methods: Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0–10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. Results: In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double-blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. Conclusion: In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD’s safety and tolerability profiles were similar to other opioid analgesics.

Pharmacokinetic Profile and Sustained 24-hour Analgesia of a Once-daily Hydrocodone Bitartrate Extended-release Tablet with Abuse-deterrent Properties.

PURPOSE The purpose of this study was to evaluate the pharmacokinetics (PK) and 24-hour analgesic effectiveness of once-daily, single-entity, extended-release hydrocodone (HYD) with abuse-deterrent properties. METHODS Four studies were included. Three open-label PK studies had the following designs: single-dose, 5-treatment, 4-period, crossover, dose-proportionality study; HYD 120 mg for 5 days (steady-state study 1); 2-treatment, 2-period, multiple-dose crossover study assessing the relative bioavailability of HYD 30 mg and hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours (steady-state study 2). A long-term, open-label study assessed the safety and effectiveness of HYD 20 to 120 mg in patients during a 52-week maintenance period. FINDINGS Thirty-one, 25, and 22 healthy subjects completed the dose-proportionality study, steady-state study 1, and steady-state study 2, respectively, while 410 patients with moderate to severe chronic nonmalignant and non-neuropathic pain completed the long-term effectiveness study. Mean systemic exposure and peak plasma concentration were dose proportional after administration of single doses of HYD 20 to 120 mg. Pharmacokinetic profiles were comparable at day 1 and day 5 after administration of HYD 120 mg once daily. Once-daily HYD 30 mg was associated with lower-fluctuating plasma hydrocodone concentrations compared with immediate-release hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours. In the long-term study, pain control was consistent over the 24-hour dosing interval. IMPLICATIONS Once-daily HYD exhibits linear, dose-proportional PK properties and is associated with a lower variability in plasma hydrocodone concentrations when compared with an immediate-release hydrocodone combination product. Notably, analgesia provided by HYD is sustained during the 24-hour dosing interval. ClinicalTrials.gov identifier: NCT01400139 (Study 4).

Long-term effectiveness and safety of once-daily, single-entity, extended-release hydrocodone in patients of ≥75 years of age with moderate to severe nonmalignant and nonneuropathic pain.

ABSTRACT In elderly (≥75 years) individuals, age‐associated physiologic changes and a higher prevalence of comorbidities, polypharmacy, and increased susceptibility to medication‐induced side effects complicate pain management. Hysingla® ER (HYD) is a once‐daily, single‐entity, extended‐release hydrocodone formulation approved for the treatment of chronic pain that is insufficiently controlled by alternative treatments. In this post‐hoc analysis of a previously reported study, the effectiveness and safety of HYD for the treatment of moderate‐to‐severe chronic pain among the elderly (≥75 years) for a 52‐week duration was investigated. HYD dose administered during the maintenance period‐remained relatively stable and provided clinically meaningful decreases in mean “pain over the last 24 h” and pain interference scores. Patients achieved pain control without additional non‐study opioid use at the end of the study. Adverse events were typical of opioids. In summary, HYD provided clinically meaningful reduction of pain scores in elderly patients that were maintained over a 52‐week period.

Long-term safety and effectiveness of once-daily, single-entity, extended-release hydrocodone over 76 weeks of an open-label study in patients with chronic noncancer and nonneuropathic pain.

Abstract Objective: To evaluate long-term use of Hysingla® ER (HYD), a single-entity, extended-release, once-daily hydrocodone bitartrate tablet with abuse-deterrent properties in patients with moderate-to-severe chronic noncancer and nonneuropathic pain. Methods: This open-label study consisted of a dose-titration period (up to 45 days), a 52-week maintenance period and a 24-week extension period. Opioid-naïve or opioid-experienced patients with controlled or uncontrolled chronic pain conditions were treated with HYD 20–120 mg daily. Supplemental nonopioid and short-acting opioid analgesics were permitted. This paper presents the results of 106 patients who continued HYD treatment for up to 76 weeks. Primary safety measures included the incidence of adverse events, as well as audiologic, clinical laboratory and electrocardiogram measurements. Effectiveness was measured by the change between baseline and the overall 76-week treatment period in “average pain over the last 24 h” (0 = no pain, 10 = pain as bad as you can imagine), Brief Pain Inventory-Short Form survey, Medical Outcomes Study 36-Item Short Form Health Survey, Medical Outcomes Study Sleep Scale-Revised and concomitant nonstudy opioid analgesic use. Results: Among 410 patients who completed the maintenance period, 106 continued into the extension. Of these, 83 (78%) completed the entire 76-week treatment period. Treatment-emergent adverse events were typical of those observed with μ-opioid agonists. No study drug abuse or diversion was reported. Clinically important analgesia and functional improvement were achieved during the dose-titration period and were maintained in most patients throughout 76 weeks without the need for continued HYD dose increases or changes in concomitant nonstudy opioid analgesics. The mean pain score was 6.1 at baseline, 3.8 at the end of the dose titration period and 3.8 through 76 weeks. Conclusions: HYD was generally well tolerated. No unexpected safety concerns emerged. Pain control was sustained throughout 76 weeks of treatment.

Effectiveness and Safety of Once-Daily Extended-Release Hydrocodone in Individuals Previously Receiving Immediate-Release Oxycodone for Chronic Pain

Abstract Objectives This study evaluated the safety and effectiveness of a once-daily, single-entity, extended-release hydrocodone bitartrate (HYD) among patients with chronic noncancer and non-neuropathic pain who required opioid rotation from a previous analgesic regimen that primarily consisted of immediate-release (IR) oxycodone. Methods Post hoc analyses of a primary study that assessed HYD 20 to 120 mg over a 52-week period are presented. The primary study included a dose titration period (up to 45 days), a 52-week maintenance period, and an optional taper period (up to 14 days). Results Relative to baseline, mean “average pain over the last 24 hours” declined by 1.9 points at the end of the titration period and by 2.6 points at the end of the maintenance period. Additionally, interference and severity of pain as measured by the Brief Pain Inventory–Short Form decreased by 2.3 and 1.9 points, respectively, during the maintenance period. The use of supplemental opioid analgesics decreased. Most patients remained on a stable HYD dose throughout the maintenance period. Most patients indicated satisfaction with HYD and considered it convenient and easy to use. HYD demonstrated a safety profile typical of µ opioids; nausea, constipation, vomiting, and dizziness were the most frequently reported opioid-related adverse events during the study. Conclusions In patients with chronic pain who received HYD over a 52-week period, treatment was generally well tolerated and provided effective analgesia among those who rotated from a pain regimen primarily consisting of IR oxycodone.

Safety and effectiveness of once daily Hysingla extended-release tablets in patients with baseline depression or anxiety

AIM Long-term safety and effectiveness of a once-daily, single-entity, extended-release formulation of hydrocodone bitartrate (HYD) for the treatment of moderate to severe noncancer and nonneuropathic pain among patients with and without concurrent depression/anxiety at baseline. MATERIALS & METHODS Post hoc analysis. RESULTS HYD demonstrated a safety profile consistent with μ-opioid agonists: Serious adverse events in 12% patients with depression/anxiety including four deaths; 6% without depression/anxiety including one death. All pain scores declined by ≥2 points and mean daily HYD dose remained stable in both subgroups. CONCLUSION More serious adverse events occurred among patients with comorbid depression/anxiety at baseline than among those without. HYD provided stable and effective analgesia for 52 weeks among chronic pain patients with and without comorbid depression/anxiety at baseline.

Efficacy and Safety of Once-Daily Extended-Release (ER) Hydrocodone in Individuals Previously Receiving ER Morphine for Chronic Pain

This post hoc analysis examined the effectiveness and safety of hydrocodone bitartrate (HYD) in patients with moderate‐to‐severe chronic pain who were previously taking extended‐release morphine (morphine ER) for pain management.