J. Young

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.

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.

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.

Comparison of single-dose and multiple-dose pharmacokinetics between two formulations of hydrocodone bitartrate/acetaminophen: immediate-release versus biphasic immediate- release/extended release

Objective This study aimed to compare the single-dose and steady-state pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) and IR HB/APAP. Setting The study was conducted in a contract research center. Participants The study included healthy adults. Interventions In a three-way crossover study, Study 1, participants received the following treatments: (A1) a single dose of IR/ER HB/APAP 7.5/325 mg one tablet, followed by one tablet every 12 hours (q12h); (B1) a single dose of IR/ER HB/APAP 7.5/325 mg two tablets, followed by two tablets q12h; (C1) a single dose of IR HB/APAP 7.5/325 mg two tablets (one tablet at hours 0 and 6), followed by one tablet q6h. In a two-way crossover study, Study 2, participants received the following treatments: (A2) an initial dose of IR/ER HB/APAP 7.5/325 mg three tablets, followed by two tablets q12h; (B2) three doses of IR HB/APAP 7.5/325 mg one tablet q4h, followed by one tablet q6h. Main outcome measures PK values were compared, and adverse events were assessed. Results Single-dose and steady-state area under the concentration–time curves for hydrocodone and APAP were similar for IR/ER and IR HB/APAP; the steady-state peak plasma concentrations (Cmax) at steady state were also similar, but single-dose Cmax for hydrocodone was lower for IR/ER HB/APAP. For most PK parameters, 90% confidence intervals for geometric least squares mean ratios were not meaningfully different (80%–125%). Steady state was achieved in 2−3 days for IR/ER HB/APAP and in 2 days for IR HB/APAP. Median time to Cmax was longer for IR/ER HB/APAP versus IR HB/APAP (P,0.05). Adverse events were similar across treatments. Conclusion PK outcomes and tolerability were similar for IR/ER HB/APAP and IR HB/APAP.

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).

Single- and multiple-dose pharmacokinetics of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) compared with immediate-release hydrocodone bitartrate/ibuprofen and immediate-release tramadol HCl/acetaminophen

Objective To characterize the single-dose and steady-state pharmacokinetics (PK) of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (IR/ER HB/APAP), IR HB/ibuprofen, and IR tramadol HCl/APAP. Methods In this single-center, open-label, randomized, four-period crossover study, healthy participants received four treatments under fasted conditions: 1) a single dose of two IR/ER HB/APAP 7.5/325 mg tablets (15/650 mg total dose) on day 1, followed by two tablets every 12 hours (q12h) beginning on day 3; 2) a single dose of IR HB/ibuprofen 15/400 mg (divided as one 7.5/200 mg tablet at hour 0 and 6), followed by one tablet every 6 hours (q6h) beginning on day 3; 3) a single dose of IR tramadol HCl/APAP 75/650 mg (divided as one 37.5/325 mg tablet at hour 0 and 6), followed by one tablet q6h beginning on day 3; and 4) a single dose of three IR/ER HB/APAP 7.5/325 mg tablets (22.5/975 mg total dose) on day 1, a three-tablet initial dose at 48 hours followed by two-tablet doses q12h beginning on day 3. Hydrocodone and APAP single-dose and steady-state PK were assessed. Adverse events were monitored. Results The PK analysis was carried out on 29 of 48 enrolled participants who completed all treatment periods. Single-dose hydrocodone exposure was similar for IR/ER HB/APAP 22.5/975 mg and IR HB/ibuprofen 15/400 mg; time to maximum observed plasma concentration was shorter and half-life was longer for IR/ER HB/APAP (22.5/975 mg and 15/650 mg) vs IR HB/ibuprofen. Single-dose APAP exposure was similar for IR/ER HB/APAP 15/650 mg and IR tramadol HCl/APAP 75/650 mg. Steady-state hydrocodone and APAP exposures were similar between treatments. Adverse events were similar for each treatment and typical of low-dose combination opioid analgesics. With dosing q12h, IR/ER HB/APAP had half as many concentration peaks and troughs as the comparators treated q6h. Conclusion With dosing q12h, IR/ER HB/APAP provided similar peak and total steady-state hydrocodone and APAP exposure vs IR comparators.

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.