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

OBJECTIVES: To characterize the safety of immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP). METHODS: Data were assessed from 9 phase 1 trials in healthy volunteers and recreational users of prescription opioids (N = 405), including 5 single-dose and 3 multidose open-label pharmacokinetic studies of IR/ER OC/APAP and active comparators; and 1 randomized, controlled, single-dose human abuse potential (HAP) study comparing IR/ER OC/APAP, IR OC/APAP, and placebo in recreational users of opioids; and 2 phase 3 trials (N = 701) including a 48-hour placebo-controlled safety and efficacy study in patients with moderate to severe postbunionectomy pain with a 14-day open-label safety extension and a long-term (≤ 35 days) open-label safety study in patients with chronic osteoarthritis pain or chronic low back pain. RESULTS: Adverse events (AEs) experienced by ≥ 10% of participants receiving IR/ER OC/APAP in all trials were pruritus, nausea, vomiting, dizziness, headache, and somnolence; these AEs occurred with similar frequency for equianalgesic doses of IR OC/APAP and IR OC but less frequently for IR tramadol HCl/APAP. In the HAP study, crushing IR/ER or IR OC/APAP tablets did not increase frequency of AEs. Constipation was experienced by < 10% of participants receiving IR/ER OC/APAP. No serious (SAE) or severe AEs were reported in phase 1 trials. In phase 3 trials of 8 reported SAEs, only 1 treatment-related SAE (hypersensitivity to placebo) required treatment discontinuation. No clinically meaningful changes in vital signs, oxygen saturation, electrocardiograms, or laboratory values were reported. CONCLUSIONS: Safety and tolerability of IR/ER OC/APAP are similar to other low-dose opioid/APAP analgesics.

Correlation of Subjective Effects with Systemic Opioid Exposure from Fixed-Dose Combinations of Oxycodone/Acetaminophen in Recreational Users of Prescription Drugs.

OBJECTIVE: To correlate abuse-related pharmacodynamic measures and pharmacokinetic measures after administering immediate-release/extended-release and immediate-release oxycodone/acetaminophen fixed-dose combination analgesicsDesign. Randomized, double-blind, active- and placebo-controlled, 7-way crossover studySetting. Contract research organizationSubjects. Nondependent recreational users of prescription opioids. METHODS: Participants received single doses of intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 15/650 mg, intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, and placebo. Measures of pharmacodynamics (pupillometry, drug liking, drug high, good drug effects) and pharmacokinetics were assessed predose and up to 24 hours postdose, and correlations between pharmacokinetic parameters and pharmacodynamic data were explored. RESULTS: Of 61 participants, 55 completed all 7 treatments. Intact immediate-release/extended-release oxycodone/acetaminophen produced 50% lower oxycodone peak plasma concentration (Cmax) than immediate-release oxycodone/acetaminophen. Median oxycodone time to Cmax (tmax) was significantly longer (P<0.001) for intact immediate-release/extended-release oxycodone/acetaminophen than immediate-release oxycodone/acetaminophen. The pharmacokinetics of crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen (30/1,300 mg) followed a similar pattern. Crushing did not shorten the median oxycodone tmax for immediate-release/extended-release oxycodone/acetaminophen (30/1,300 mg). Strong correlations were observed between oxycodone Cmax and area under the curve from time 0 to time x peak effects and area under the subjective effect curve from time 0 to time x for all subjective effects (R2=0.711-0.997). CONCLUSION: Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone Cmax and longer tmax than immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects.

Single-dose pharmacokinetics of 2 or 3 tablets of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) under fed and fasted conditions: two randomized open-label trials.

BACKGROUND: Biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) 7.5/325-mg tablets are formulated with gastroretentive ER drug delivery technology that has been associated with clinically meaningful food effects in other approved products. Two phase 1 studies evaluated potential effects of food on single-dose pharmacokinetics of IR/ER HB/APAP tablets. METHODS: These were single-center, open-label, randomized, single-dose, 3-period crossover studies in healthy volunteers (aged 18-55 years). IR/ER HB/APAP was administered as a single 2-tablet dose (study 1) or 3-tablet dose (study 2) under fed (high- and low-fat) and fasted conditions. Area under the plasma concentration-time curve from 0 h to time t (AUC0-t) and from time 0 extrapolated to infinity (AUC0-inf) and maximum observed plasma concentration (Cmax) of hydrocodone and APAP under fed versus fasted conditions were compared using analysis of variance. A 90% confidence interval of the geometric least squares mean ratio fully contained within 80 to 125 % indicated no treatment difference. Safety and tolerability were assessed. RESULTS: Forty of 48 participants in study 1 and 21 of 30 in study 2 completed all treatments. In both studies, under fed (high- or low-fat meal) versus fasted conditions, 90% CIs for AUC0-t and AUC0-inf for both hydrocodone and APAP were entirely contained within the bioequivalent range (80-125%), indicating that high- and low-fat meals did not affect the extent of exposure. In both studies, a high-fat meal did not affect the Cmax for hydrocodone. Hydrocodone Cmax was not affected by a low-fat meal in study 1 but increased by approximately 19% in study 2. A high-fat meal decreased APAP Cmax by approximately 20 % (study 1) and 13 % (study 2); a low-fat meal decreased APAP Cmax by 22% (study 1) and 21% (study 2). Approximately 50% of participants in both studies reported ≥1 treatment-emergent adverse event (TEAE), with no notable difference based on food intake. There were no serious or severe AEs. The most common TEAEs were nausea, vomiting, and dizziness. CONCLUSIONS: Pharmacokinetic and safety findings were similar regardless of food intake. TEAEs were consistent with those reported with low-dose combination opioids. IR/ER HB/APAP can be administered without regard to food. TRIAL REGISTRATION: ClinicalTrials.gov NCT02561650 and NCT02561741 .

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.

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 (C max) at steady state were also similar, but single-dose C max 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 C max 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.

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 Hy's 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.

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.

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.

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

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 (E(max)); time to peak effects (TE(max)); 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 E(max) (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.

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: 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.

Comparison of subjective effects of extended-release versus immediate-release oxycodone/acetaminophen tablets in healthy nondependent recreational users of prescription opioids: a randomized trial.

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.

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: 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.