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(PDF) Download www.scottishmedicines.org.uk SMC2242 naldemedine 200 micrograms film-coated tablets (Rizmoic®) Shionogi BV 06 March 2020 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHSScotland. The advice is summarised as follows: ADVICE: following a full submission naldemedine (Rizmoic®) is accepted for use within NHSScotland. Indication under review: For the treatment of opioid induced constipation (OIC) in adult patients who have previously been treated with a laxative. Naldemedine compared to placebo significantly improved the spontaneous bowel movement response rate in patients with opioid induced constipation and either non-cancer or cancer pain. Chairman Scottish Medicines Consortium Published 13 April 2020 1 Indication For the treatment of opioid induced constipation (OIC) in adult patients who have previously been treated with a laxative.1 Dosing Information The recommended dose of naldemedine is 200 micrograms (one tablet) to be taken orally once daily. Naldemedine can be used with or without other laxatives, and can be taken with or without food.1 Naldemedine can be taken at any time of the day; however, it is recommended that it be taken at the same time each day. Alteration of the analgesic dosing regimen is not required. Naldemedine must be discontinued if treatment with opioids is discontinued.1 Product availability date October 2019 Summary of evidence on comparative efficacy Naldemedine is an antagonist of the mu-, delta-, and kappa-opioid receptors. It functions as a peripherally acting mu-opioid receptor antagonist within the enteric nervous system of the gastrointestinal tract. Naldemedine acts by decreasing the constipating effects of opioids without reversing the centrally mediated effects of opioids.1 Evidence supporting the efficacy and safety of naldemedine comes from COMPOSE-1 and COMPOSE-2, which were identical, phase III, double-blind, randomised, placebo-controlled, parallel-group studies. Patients aged 18 to 80 years with chronic non-cancer pain, who were taking opioids for at least 3 months at a stable total daily dose ≥30mg morphine equivalent for ≥1 month with experience of OIC were included. Patients were either not taking laxatives or agreed to discontinue any laxative before the 14-day screening period. Patients were included if they had experienced ≤4 spontaneous bowel movements (SBMs), defined as a bowel movement occurring without the use of rescue laxative medication in the previous 24 hours, within the 14-day screening period, ≤3 SBMs in any given week, and at least one bowel symptom (straining, lumpy/hard stools, sensation of incomplete evacuation/blockage) in at least 25% of bowel movements (BMs). Patients were also required to have at least 78% compliance with daily completion of electronic diary entries in the 14-day screening period.2 Patients were randomised equally to receive double-blind naldemedine 200 micrograms orally once per day (COMPOSE-1: n= 273 COMPOSE-2: n= 276) or placebo (COMPOSE-1: n=272; COMPOSE-2: n=274) for 12 weeks. Regular laxative use was not permitted throughout the treatment period. Rescue laxative therapy was initiated if a patient did not have a BM for any period of 72 hours during the treatment period. During the study, opioid doses were managed by the treating physician, and breakthrough medication (non-opioid and opioid) was allowed. 2 Randomisation was stratified by average total daily opioid dose (30 to 100mg and >100mg equivalents of oral morphine).2 The primary outcome was the proportion of responders, defined as those having ≥3 SBMs per week and an increase from baseline of ≥1 SBM per week for that week (a positive response week) for ≥9 weeks out of the 12-week treatment period and ≥3 of the last 4 weeks of the 12-week treatment period. Proportion of responders was assessed in the intention-to-treat population (ITT) which included all randomised patients.2 In COMPOSE-1 and COMPOSE-2, the proportion of responders was significantly higher in the naldemedine groups than in the placebo groups. The results are presented in Table 1. Post-hoc analyses defining the study population as inadequate response to laxatives (LIR) and adequate response to laxatives (non-LIR) patient groups showed consistent efficacy in both groups when data from COMPOSE-1 and 2 were pooled.3 Table 1. Primary outcome results of COMPOSE-1 and COMPOSE-2 (ITT population).2 COMPOSE-1 COMPOSE-2 naldemedine placebo naldemedine placebo 200mcg (n=272) 200mcg (n=274) (n=273) (n=276) Responders 130 94 145 92 Response rate 48% 35% 52% 34% Difference (95% CI) 13% (4.8% to 21%) 19% (11% to 27%) p=0.002 p<0.001 CI = confidence interval A hierarchical statistical testing strategy was applied in each study with no formal testing of outcomes after the first non-significant outcome in the hierarchy. Secondary outcomes in COMPOSE-1 and COMPOSE-2 included change in the frequency of SBMs per week from baseline to the last 2 weeks of the treatment period and from baseline to week 1 of the treatment period, change in the frequency of complete spontaneous bowel movement (CSBM), defined as a SBM with the feeling of complete evacuation, per week from baseline to the last 2 weeks of the treatment period, and change in the frequency of SBMs without straining per week from baseline to the last 2 weeks of the treatment period. In both studies, statistically significant differences in favour of naldemedine were reported for all specified secondary outcomes (Table 2).2 3 Table 2. Key secondary results of COMPOSE-1 and COMPOSE-2 (ITT population).2, 3 COMPOSE-1 COMPOSE-2 naldemedine placebo naldemedine placebo 200mcg (n=272) 200mcg (n=274) (n=273) (n=276) Change in the frequency of SBMs per week 3.4 2.1 3.6 2.2 from baseline to the last 2 weeks of the [0.2] [0.2] [0.2] [0.2] treatment period (least square mean) [SE] - Least square mean difference (95% CI) 1.3 (0.8 to 1.8) 1.4 (0.9 to 1.9) p<0.001 p<0.001 Change in the frequency of SBMs per week 3.5 1.4 3.9 1.7 from baseline to week 1 of the treatment [0.2] [0.2] [0.2] [0.2] period (least square mean) [SE] - Least square mean difference (95% CI) 2.1 (1.6 to 2.6) 2.2 (1.6 to 2.7) p<0.001 p<0.001 Change in the frequency of CSBM per week 2.5 1.6 2.8 1.6 from baseline to the last 2 weeks of the [0.2] [0.2] [0.2] [0.2] treatment period (least square mean) [SE] - Least square mean difference (95% CI) 1.0 (0.5 to 1.5) 1.2 (0.7 to 1.6) p<0.001 p<0.001 Change in the frequency of SBMs without 1.5 0.7 1.8 1.1 straining per week from baseline to the last 2 [0.1] [0.1] [0.2] [0.2] weeks of the treatment period (least square mean) - Least square mean difference (95% CI) 0.7 (0.3 to 1.1) 0.8 (0.3 to 1.2) p<0.001 p=0.0011 CI= confidence interval; CSBM= complete spontaneous bowel movement; SBM= spontaneous bowel movement; SE= standard error In COMPOSE-1, 2, and 3, the patient assessment of constipation symptoms (PAC-SYM) and the patient assessment of quality of life (PAC-QOL) questionnaires were completed at baseline, week 2, 4 and 12 (plus week 24, 36, and 52 for COMPOSE-3). Improvements in PAC-SYM and PAC-QOL scores of greater than 0.8 and 1 respectively are deemed clinically relevant.3 In COMPOSE-1, 2 and 3, patients receiving naldemedine 200micrograms experienced greater improvements from baseline to week 12 compared with placebo in PAC-SYM and PAC-QOL scores: mean change from baseline to week 12 in PAC-SYM overall score (naldemedine group) = -0.93, -1.01, and -1.11 (least squares mean) respectively; mean change from baseline to week 12 in PAC-QOL overall score (naldemedine group) = -0.93, -1.08, and -1.19 (least squares mean).3, 5-7 COMPOSE-3 was a randomised, double-blind, placebo-controlled, parallel-group, phase III study that examined the long-term efficacy of naldemedine (200micrograms once daily orally) versus placebo for 52 weeks in a population of 1,246 patients (623 patients in each group) with chronic non-cancer pain who were on a stable opioid regimen and diagnosed with OIC. Patients had no more than 4 SBMs total over the 14-consecutive-day qualifying period, as well as no more than 3 SBMs in a given week of the qualifying period. Patients on a stable laxative regimen at screening 4 could continue this treatment during the study. Laxative therapy was provided for patients who required laxatives (as a stable regimen or as rescue) during the screening and treatment periods.3, 9 Efficacy outcomes were secondary outcomes in COMPOSE-3, and included change in frequency of bowel movements from baseline, measured at 12, 24, 36 and 52 weeks and quality of life outcomes. The study demonstrated an increase in the frequency of bowel movements in the naldemedine group compared with placebo, with a treatment difference of 1.3 BMs per week at week 12. This difference was sustained through Week 52.3, 9 Patients in the naldemedine group had a greater improvement from baseline in the mean overall PAC-SYM score over time than patients in the placebo group. Secondary efficacy outcomes were analysed for the subgroup of patients on or not on a stable laxative regimen.
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