Thomas Barrett

Comparison of Subjective Effects of Extended-Release Versus Immediate-Release Oxycodone/Acetaminophen Tablets in Healthy Nondependent Recreational Users of Prescription Opioids: A Randomized Trial

Abstract Background: Prescription opioids have substantial abuse potential. This study compared the positive subjective drug effects of a newly developed extended-release (ER) oxycodone (OC)/acetaminophen (acetyl-para-aminophenol [APAP]) formulation with those of immediate-release (IR) OC/APAP. Methods: This randomized, double-blind, active- and placebo-controlled, 7-way crossover study enrolled healthy volunteers who were recreational prescription opioid users. The protocol was approved by an institutional review board and all participants provided written informed consent. Participants received single doses of intact ER and IR OC/APAP 15/650 mg, intact ER and IR OC/APAP 30/1300 mg, crushed ER and IR OC/APAP 30/1300 mg, and placebo. Peak subjective effects (Emax), time to Emax, and area under the drug-effect curves for drug liking, drug high, and good drug effects were measured using visual analogue scales. Least squares means with 95% confidence interval were compared using analysis of variance. Results: Among completers (N = 55), intact ER OC/APAP produced delayed and lower peak effects versus IR OC/APAP. Comparing intact tablets, the drug liking Emax (least squares means [95% confidence interval]) was significantly lower for OC/APAP 30/1300 mg (76.4 [72.8 to 80.0]) than for IR OC/APAP 30/1300 mg (85.6 [81.9 to 89.2]; difference, −9.2 [−13.1 to −5.2]; P < 0.001). Similar results were observed for intact ER and IR OC/APAP (15 mg/650 mg). Crushing ER OC/APAP 30/1300 mg further delayed these effects compared with the same dose of crushed IR OC/APAP and intact ER OC/APAP. Conclusions: Extended-release OC/APAP produced lower subjective drug effects than IR OC/APAP. Crushing ER OC/APAP further delayed onset of subjective effects compared with intact ER OC/APAP. The ER OC/APAP may be less attractive for abuse than IR OC/APAP. Clinical trial registration: This phase 1 study conducted in the United States was not registered.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of MNK-795, a dual-layer, biphasic, immediate-release and extended-release combination analgesic for acute pain

Abstract Objective: To investigate the efficacy and safety of a bilayer combination oxycodone (OC) and acetaminophen (APAP) analgesic with both immediate-release and extended-release (ER) components (OC/APAP ER) in patients with moderate to severe pain using an established acute pain model. Research design and methods: This was a randomized, double-blind, placebo-controlled trial. Adult patients were included in the study if they had a pain intensity score ≥4 on a 0–10 numerical rating scale after bunionectomy surgery, and were randomized (1:1) to receive four doses (two tablets q12h) of OC/APAP ER or placebo. Clinical trial registration: ClinicalTrials.gov identifier: NCT01484652. Main outcome measures: The primary efficacy endpoint was the summed pain intensity difference over the first 48 hours (SPID48). Secondary endpoints included SPIDs and total pain relief (TOTPAR) over the dosing intervals; time to perceptible, meaningful, and confirmed pain relief; and the proportion of patients with ≥30% reduction in pain intensity scores. Results: A total of 329 patients were enrolled, of whom 266 (OC/APAP ER, n = 135; placebo, n = 131) completed the study. The mean (SE) SPID48 was 114.9 (7.6) in the OC/APAP ER group and 66.9 (7.6) in the placebo group (P < 0.0001). SPID and TOTPAR values were significantly greater with OC/APAP ER than with placebo over all time periods analyzed, and the median times to perceptible, meaningful, and confirmed pain relief were significantly shorter. More patients showed ≥30% reduction in pain intensity scores with OC/APAP ER than with placebo at all times after 0.5 hours. OC/APAP ER was generally well tolerated. A limitation of this study was the lack of an active comparator. Conclusions: OC/APAP ER was efficacious and generally well tolerated in an established model of moderate to severe acute pain, providing an onset of analgesia in approximately 30 minutes and sustained pain relief over the 12 hour dosing period.

Pharmacokinetics and bioavailability of oxycodone and acetaminophen following single-dose administration of MNK-795, a dual-layer biphasic IR/ER combination formulation, under fed and fasted conditions

Background XARTEMIS™ XR (formerly MNK-795) is a combination oxycodone (OC) and acetaminophen (APAP) analgesic with both immediate-release and extended-release (ER) components (ER OC/APAP). The tablets are designed with gastric-retentive ER oral delivery technology that releases the ER component at a controlled rate in the upper gastrointestinal tract. Because consumption of food has demonstrated an impact on the pharmacokinetics (PK) of some marketed products using gastric-retentive ER oral delivery technology, a characterization of the effects of fed (high- and low-fat diets) versus fasted conditions on the PK of ER OC/APAP was performed. Methods This Phase I study used an open-label randomized single-dose three-period six-sequence crossover single-center design. Healthy adult participants (n=48) were randomized to receive two tablets of ER OC/APAP under three conditions: following a high-fat meal; following a low-fat meal; and fasted. Plasma concentration versus time data from predose throughout designated times up to 48 hours postdose was used to estimate the PK parameters of oxycodone and APAP. Results Thirty-one participants completed all three treatment periods. Both oxycodone and APAP were rapidly absorbed under fasted conditions. Total oxycodone and APAP exposures (area under the plasma drug concentration-time curve [AUC]) from ER OC/APAP were not significantly affected by food, and minimal changes to maximum observed plasma concentration for oxycodone and APAP were also noted. However, food marginally delayed the time to maximum observed plasma concentration of oxycodone and APAP. There was no indication that tolerability was affected by food. Conclusion The findings from this study suggest that ER OC/APAP can be administered with or without food.

Human abuse potential of immediate-release/extended-release versus immediate-release hydrocodone bitartrate/acetaminophen: a randomized controlled trial in recreational users of prescription opioids

Abstract Background. The abuse potential of prescription opioids is well established. This study compared positive, subjective drug effects of single, equal doses of biphasic immediate release (IR)/extended release (ER) hydrocodone bitartrate (HB)/acetaminophen (acetyl-p-aminophenol [APAP]) 7.5/325 mg tablets versus IR HB/APAP 7.5/325-mg tablets and placebo. Methods: Healthy adult recreational users of prescription opioids entered this randomized, double-blind, double-dummy, active- and placebo-controlled, seven-way crossover study. Participants received single, total doses of IR/ER HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), IR HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), and placebo. Peak subjective effects (Emax); time to peak effects (TEmax); and area under the drug–effect curves for drug liking, high, and good drug effects were measured using visual analog scales. Median values with 95% confidence interval (CI) were compared using analysis of variance. Results: Among completers (n = 52), IR/ER HB/APAP produced delayed and lower peak effects compared to equal doses of IR HB/APAP. Comparing intact tablets, the drug liking Emax (median [95% CI]) was significantly lower for IR/ER HB/APAP 45/1950 mg (78.0 [73.0, 81.0]) than an equal dose of IR HB/APAP (89.5 [85.0, 93.0]; difference, –8.5 [–12.0, –6.0]; P < 0.001). Similar results were observed for intact IR/ER HB/APAP and IR HB/APAP 22.5/975 mg. Crushing IR/ER HB/APAP 45/1950 mg delayed these effects compared with an equal dose of crushed IR HB/APAP and intact IR/ER HB/APAP. Conclusion. IR/ER HB/APAP resulted in lower subjective positive drug effects than an equal dose of IR HB/APAP. Crushing IR/ER HB/APAP also delayed the onset of subjective effects compared with intact IR/ER HB/APAP. These findings suggest that biphasic IR/ER HB/APAP has lower abuse potential than IR HB/APAP in single equal doses. Registration: This Phase I clinical trial conducted in the USA was not registered.

Assessment of the safety and efficacy of extended-release oxycodone/acetaminophen, for 14 days postsurgery

Abstract Objective: To investigate the safety and satisfaction of patients treated ≤14 days after unilateral bunionectomy with extended-release oxycodone/acetaminophen (ER OC/APAP), a biphasic (ER and immediate release) fixed-dose combination analgesic being developed for moderate to severe acute pain. Research design and methods: This was an open-label extension (OLE) of a randomized, double-blind, placebo-controlled trial (DBRCT) of patients undergoing bunionectomy. Patients who consented to the OLE before entering the 48 hour DBRCT entered the OLE upon completing the DBRCT and during the OLE received two tablets of ER OC/APAP (15/650 mg total dose) every 12 hours for ≤14 days. ClinicalTrials identifier: ClinicalTrials.gov identifier: NCT01484652. Main outcome measures: Treatment-emergent adverse events, physical examinations, vital sign measurements, and clinical laboratory testing were assessed throughout the study. Global assessments of treatment satisfaction were made at the end of the DBRCT and at each clinic visit during the OLE. Results: A total of 146 patients consented to the OLE before entering the DBRCT and 129 completed the OLE. Tolerability of ER OC/APAP during the OLE was consistent with that of an opioid product. Adverse events occurred during the OLE in 64 patients (43.8%); the most common were gastrointestinal events including nausea (17.8%), vomiting (7.5%), and constipation (6.2%). No changes in vital signs or clinical laboratory tests were considered by the investigator to be clinically significant. At all visits during the OLE, the majority of patients were satisfied or very satisfied with their medication. Limitations include a 14 day postprocedure study duration that may be confounded with natural healing time, and lack of a placebo arm. Conclusions: These results show that ER OC/APAP demonstrated an expected safety and tolerability profile and good patient satisfaction in a postsurgical model of acute pain.

Evaluation of the tamper-resistant properties of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

Abstract Context: Abuse potential of extended-release (ER) opioid tablets increases if tampering causes rapid opioid release. Objective: To evaluate the susceptibility to tampering of biphasic immediate-release (IR)/ER oxycodone (OC)/acetaminophen (APAP) tablets compared with IR OC/APAP tablets. Materials and methods: IR/ER OC/APAP and IR OC/APAP tablets were tested at room temperature and after heating, freezing and microwaving. Resistance to crushing was tested using manual and powered tools (e.g. spoons, mortar and pestle, blender, coffee grinder). Tampered tablets were tested for suitability for snorting, OC extraction in solvents and ease of drawing into a syringe. Dissolution of IR/ER OC/APAP in gastric fluid with and without ethanol was tested to determine the potential for facilitating precipitous release of opioid from the tablet. Results: IR/ER OC/APAP tablets were more crush resistant than IR OC/APAP tablets. Heating, freezing and microwaving had no effect on crush resistance of IR/ER OC/APAP tablets. Although a mortar and pestle pulverized IR/ER OC/APAP tablets, upon contact with solvent, the powder formed a thick gel judged unsuitable for absorption through the nasal mucosa and could not be drawn into a syringe. In contrast, powder from crushed IR OC/APAP tablets dissolved readily, was judged suitable for snorting, and was easily drawn into a syringe. Dissolution of IR/ER OC/APAP tablets in gastric fluid was slowed by the addition of ethanol. Discussion: IR/ER OC/APAP tablets are resistant to crushing and dissolution compared with IR OC/APAP tablets. Conclusion: IR/ER OC/APAP tablets may have less potential for abuse involving tampering compared with IR OC/APAP tablets.

Randomized, double-blind, placebo-controlled study of the efficacy and safety of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen tablets for acute postoperative pain

Abstract Background. A fixed-dose combination biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) tablet is being developed for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate. Methods. This Phase III, randomized, double-blind, placebo-controlled, parallel-group study evaluated the analgesic efficacy and safety of IR/ER HB/APAP (n = 201) versus placebo (n = 202) over a period of 48 hours in patients with acute moderate to severe pain following unilateral bunionectomy. Patients received three tablets of placebo or IR/ER HB/APAP as an initial dose (hour 0) followed by two tablets every 12 hours for a total daily dose of 37.5/1625 mg HB/APAP on day 1 and 30/1300 mg HB/APAP thereafter. The primary efficacy outcome was the summed pain intensity difference (SPID) over the first 48 hours (SPID48) after the first dose. Results. SPID48 was significantly greater with IR/ER HB/APAP versus placebo (p < 0.001). SPID dosing interval analyses demonstrated consistent, superior pain relief with IR/ER HB/APAP for each dosing interval (all p < 0.001). Mean PID was greater with IR/ER HB/APAP versus placebo beginning 30 minutes after the first dose (p < 0.05), and IR/ER HB/APAP demonstrated faster median time to the onset of perceptible, meaningful, and confirmed pain relief (all p < 0.001). Mean total pain relief scores also indicated greater pain relief with IR/ER HB/APAP versus placebo throughout the 48-hour period (p = 0.012) for all comparisons. A greater proportion of IR/ER HB/APAP versus placebo patients was either “very satisfied” or “satisfied” with their pain relief (69.3% vs 49.4%; p < 0.001). Nausea was the most common treatment-emergent adverse event (TEAE; IR/ER HB/APAP, 25%; placebo, 7.9%). All TEAEs in IR/ER HB/APAP–treated patients were mild or moderate in severity. Conclusion. IR/ER HB/APAP provided rapid, significant, and consistent analgesic efficacy over a period of 48 hours in an established model of acute pain and was tolerated with a safety profile similar to other low-dose opioids.

Biodistribution of diclofenac following repeated topical applications of two diclofenac sodium formulations to minipigs

This study evaluated diclofenac concentrations in plasma, selected hind limb tissues and synovial fluid after repeated topical applications of two diclofenac formulations. Group 1 Gottingen minipigs (n = 18) were administered diclofenac sodium 2.0% topical solution twice daily on days 1–6 and once on day 7. Group 2 minipigs (n = 18) were administered diclofenac sodium 1.5% topical solution four times daily on days 1–6 and twice on day 7. Approximately 20 mg of diclofenac was applied daily to a 10 × 15 cm dosing site centered over the patella of the right knee. Plasma and tissue samples were collected throughout and analysed for diclofenac concentrations using liquid chromatography with tandem mass spectrometry. On day 1, diclofenac sodium 2.0% topical solution produced higher plasma concentrations compared with the 1.5% formulation; however, after 24 h and throughout the remainder of the dosing period, plasma concentrations appeared similar, except at the 72 h time point. Twenty‐four hours after the final application, skin treated with diclofenac sodium 2.0% topical solution retained a significantly (p < 0.02) greater amount of diclofenac than the 1.5% formulation. Generally, both formulations produced similar diclofenac concentrations in synovial fluid, underlying muscle, tendon and bone 24 h after the last application. The 2.0% diclofenac formulation applied twice daily delivered similar amounts of diclofenac as the 1.5% formulation administered four times daily. The skin retained a significant portion of the applied dose to serve as a depot for continuous diffusion of diclofenac into underlying tissues and systemic circulation. Copyright

Safety and Tolerability of Biphasic Immediate‐Release/Extended‐Release Oxycodone/Acetaminophen Tablets: Analysis of 11 Clinical Trials

To characterize the safety of immediate‐release (IR)/extended‐release (ER) oxycodone (OC)/acetaminophen (APAP).

Tolerability of Biphasic-Release Hydrocodone Bitartrate/Acetaminophen Tablets (MNK-155): A Phase III, Multicenter, Open-Label Study in Patients With Osteoarthritis or Chronic Low Back Pain

PURPOSE This study aimed to assess the tolerability of the extended use (≤35 days) of MNK-155, a biphasic (immediate-release/extended-release) hydrocodone bitartrate/N-acetyl-p-aminophenol (acetaminophen) (IR/ER HB/APAP) 7.5/325-mg fixed-dose combination analgesic agent, in patients with chronic noncancer pain (CNCP) caused by osteoarthritis or chronic low back pain. IR/ER HB/APAP tablets deliver 25% of the HB dose and 50% of the APAP dose by IR and the remainder by ER over a 12-hour dosing interval. Although IR/ER HB/APAP is being developed for the management of moderate to severe acute pain, this model of CNCP was used for assessing tolerability over a term longer than would be possible in a model of acute pain. METHODS This Phase III, multicenter, open-label study enrolled patients with moderate to severe OA (knee or hip) pain despite the use of nonopioid or opioid analgesic agents, or with moderate to severe CLBP present for several hours per day for ≥3 months. Patients received a 3-tablet initial dose of IR/ER HB/APAP (total dose, 22.5/975 mg) on day 1, followed by 2 tablets of IR/ER HB/APAP (total dose, 15/650 mg) q12h for up to 35 days. Tolerability, the primary end point, was assessed using time to treatment discontinuation, the prevalence of treatment-emergent adverse events (TEAEs), vital sign measurements, pulse oximetry, clinical laboratory tests, and compliance. Secondary outcomes included the modified Brief Pain Inventory-Short Form, the Western Ontario and McMaster Universities Arthritis Index, and The Roland-Morris Low Back Pain and Disability Questionnaire. FINDINGS Of the 153 patients enrolled (95 women [62.1%]; mean age, 53.9 [14.5] years; OA, n = 73; CLBP, n = 80), 37 (24.2%) discontinued the study early (mean time to discontinuation, 21.3 days). Thirteen patients (8.5%) discontinued because of TEAEs. A total of 88 patients (57.5%) reported ≥1 TEAE, 65 (42.5%) of whom experienced AEs considered by the investigator as treatment related. The most frequent TEAEs were nausea (16.3%), somnolence (14.4%), and constipation (11.1%). Eight severe TEAEs were experienced by 6 (3.9%) patients and included single occurrences of nausea, fatigue, nasopharyngitis, elevated liver enzymes, headache, nightmare, and ejaculation delay. No serious treatment-related AEs were reported. Clinically significant changes in laboratory values were reported in 13 patients, 6 of whom had abnormal liver function test results that did not meet Hys law criteria for acute liver failure. Most laboratory abnormalities were mild and transient. Measures of pain intensity, function, and quality of life improved from baseline but in an open-label study these changes cannot be attributed to treatment. IMPLICATIONS The safety profile of IR/ER HB/APAP during extended use was consistent with those of other low-dose opioid/APAP combination products. IR/ER HB/APAP is intended for acute pain; its efficacy for relief of CNCP would require further evaluation in an active- or placebo-controlled study. ClinicalTrials.gov Identifier: NCT01722864.