Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Shionogi B.V., Kingsfordweg 151, 1043GR Amsterdam, The Netherlands
Pharmacotherapeutic group: Drugs for constipation, peripheral opioid receptor antagonists
ATC code: A06AH05
Naldemedine is an antagonist of opioid binding at the mu-, delta-, and kappa-opioid receptors. Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without reversing the central nervous system (CNS)-mediated opioid effects.
Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB); the CNS penetration of naldemedine is expected to be negligible at the recommended dose. Additionally, naldemedine is a substrate of the P-glycoprotein (P-gp) efflux transporter, which may also be involved in reducing naldemedine penetration into the CNS. Based on this, naldemedine is expected to exert its anti-constipating effects on opioids without reversing their CNS-mediated analgesic effects.
The efficacy and safety of naldemedine has been established in patients with chronic non-cancer pain and OIC and in patients with cancer and OIC.
The safety and efficacy of naldemedine was evaluated in two identical, 12-week randomised, doubleblind placebo-controlled trials (Studies V9231 and V9232) in which naldemedine was used without laxatives and in a third long-term 52-week randomised, double-blind placebo-controlled trial (Study V9235) in which naldemedine was used with or without stable laxatives in patients with chronic noncancer pain and OIC.
Patients receiving a stable opioid morphine equivalent daily dose of ≥30 mg for at least 4 weeks before enrollment and self-reported OIC were eligible to participate.
In Studies V9231 and V9232, OIC was confirmed through a 2-week run-in period and was defined as no more than 4 spontaneous bowel movements (SBMs) total over 14 consecutive days and <3 SBMs in a given week with at least 25% of the SBMs associated with one or more of the following conditions: (1) straining, (2) hard or lumpy stools; (3) having a sensation of incomplete evacuation; and (4) having a sensation of anorectal obstruction/blockage. In Study V9235, OIC was confirmed through a 2-week run-in period and was defined as no more than 4 SBMs total over 14 consecutive days and <3 SBMs in a given week.
A SBM was defined as a bowel movement (BM) without rescue laxative taken within the past 24 hours.
In Studies V9231 and V9232, patients had to either not be using laxatives or be willing to discontinue laxative use at the time of Screening and be willing to use only the provided rescue laxatives during the Screening and Treatment Periods. All study participants took laxatives previously for the treatment of OIC. In Study V9235, patients on a stable laxative regimen at screening (52.4%) were allowed to continue using that same regimen without change throughout the study duration. In the run-in and treatment periods for all three studies, bisacodyl was used as rescue laxative if patients had not had a BM for 72 hours and were allowed one-time use of an enema if after 24 hours of taking bisacodyl, they still had not had a BM.
Patients with evidence of significant structural abnormalities of the gastrointestinal tract were not enrolled in these studies.
A total of 547 patients in Study V9231, 551 patients in Study V9232 and 1246 patients in Study V9235 were randomised in a 1:1 ratio to receive 200 micrograms of naldemedine or placebo once daily for 12 weeks for Studies V9231 and V9232, for 52 weeks for Study V9235.
In Studies V9231, V9232 and V9235, the mean age of the subjects in these three studies was 53.2 years; 14.8% were 65 years of age or older; 62.0% were women; 80.2% were white.
In Study V9231, the three most common types of pain were back pain (62.0%); neck pain (8.3%) and osteoarthritis (5.3%). In Study V9232, they were back pain (53.6%); pain (10.2%) and arthralgia (7.8%). In Study V9235, the three most common types of pain were back pain (58.0%); osteoarthritis (9.5%) and neck pain (8.1%).
Prior to enrollment, patients had been using their current opioid for an average of 5 years. The patients who participated in Studies V9231, V9232 and V9235 were taking a wide range of opioids. The mean baseline opioid morphine equivalent daily dosage was 132.42 mg, 120.93 mg, and 122.06 mg per day for Studies V9231, V9232 and V9235 respectively. The mean baseline SBMs was 1.31, 1.17, and 1.60, for Studies V9231, V9232 and V9235 respectively.
The primary endpoint for Studies V9231 and V9232 was the proportion of SBM responders, defined as: ≥3 SBMs per week and a change from baseline of ≥1 SBM per week for at least 9 out of the 12 study weeks and 3 out of the last 4 weeks. The primary efficacy endpoint for Study V9235 was the change in the frequency of BMs per week from baseline to Weeks 12, 24, 36 and 52.
There was a statistically significant difference for naldemedine treatment group versus placebo for the primary endpoint in Studies V9231 and V9232 (see Table 3).
There were 4 secondary endpoints in Studies V9231 and V9232 (see Table 3).
Table 3. Clinical outcomes for studies V9231 and V9232:
| V9231 | V9232 | |||
|---|---|---|---|---|
| Naldemedine (N=273) | Placebo (N=272) | Naldemedine (N=276) | Placebo (N=274) | |
| Proportion of SBM Responders | 47.6% | 34.6% | 52.5% | 33.6% |
| Treatment difference | 13.0% (95% CI: 4.8%, 21.3%, p=0.0020*) | 18.9% (95% CI: 10.8%, 27.0%, p <0.0001*) | ||
| Change in frequency of SBMs per week (LS Mean) | ||||
| From baseline to the last 2 weeks of treatment** | 3.42 | 2.12 | 3.56 | 2.16 |
| From baseline to week 1** | 3.48 | 1.36 | 3.86 | 1.69 |
| Change in frequency of CSBMs per week (LS Mean) | ||||
| From baseline to the last 2 weeks of treatment** | 2.58 | 1.57 | 2.77 | 1.62 |
| Change in frequency of SBMs without straining per week (LS Mean) | ||||
| From baseline to the last 2 weeks of treatment*** | 1.46 | 0.73 | 1.85 | 1.10 |
CI=Confidence Interval
* Statistically significant: p-values based on the Cochran-Mantel-Haenszel test.
** p <0.0001
*** p=0.0003 for study V9231 and p=0.0011 for study V9232
For Study V9235, the efficacy of naldemedine vs. placebo was assessed as secondary endpoints by the frequency of BMs as presented in Table 4.
Table 4. Change in the frequency of BMs per week from baseline to each visit (LS Mean) ITT population in study V9235:
| Naldemedine (N=621) | Placebo (N=620) | |
|---|---|---|
| Mean frequency of BMs at baseline | 2.02 | 2.02 |
| Change in the Frequency of BMs per week | ||
| Week 12* | 3.70 | 2.42 |
| Week 24* | 3.77 | 2.77 |
| Week 36* | 3.88 | 2.88 |
| Week 52* | 3.92 | 2.92 |
* nominal p ≤0.0001
The efficacy and safety were also assessed in the laxative inadequate responders (LIR) and non-LIR subgroups.
In Studies V9231 and V9232, patients who, based on concomitant medication records, were on laxative therapy prior to entering the study and who stopped its use within 30 days prior to Screening, and had self-reported OIC, were considered to be a LIR.
Additionally, patients who were not on laxatives within 30 days prior to Screening and only received rescue laxative at or after Screening were considered non-LIR. The number of patients in the LIR and non-LIR subgroups were 629 (naldemedine: 317 and placebo: 312) and 451 (naldemedine: 223 and placebo: 228) for pooled Studies V9231 and V9232. All study participants took previous laxatives at some time for the treatment of OIC prior to entering the trials V9231 or V9232.
In the LIR subgroup, a greater proportion of responders was observed with naldemedine (46.4%) compared with placebo (30.2%) and the difference between groups (16.2%) was statistically significant (p<0.0001).
In the non-LIR subgroup, consistent with the results in the LIR subgroup, a greater proportion of responders was observed with naldemedine (54.3%) compared with placebo (38.9%) and the difference between groups (15.6%) was statistically significant (p=0.0009). For Study V9235, long term efficacy data defined as the change in frequency of BMs at week 52 from baseline, assessed as a secondary endpoint, showed that subjects in the naldemedine group had improvements in the frequency of BMs compared with subjects in the placebo group in both LIR (3.10 vs 1.90, p=0.0210) and non-LIR (4.26 vs 3.39, p=0.1349) subgroups.
The safety and efficacy of naldemedine was also evaluated in 2 randomised, double-blind and placebocontrolled studies (V9222 and V9236) in patients with cancer and OIC.
Subjects were required to be treated with opioids for ≥14 days prior to Screening and had to be receiving a stable dose. The studies included a 2-week Screening Period, 2-week Treatment Period and 4-week Follow-up Period. For patients receiving laxative therapy at the Screening visit, it had to be continued at a stable dose until the end of the Treatment Period. Patients were allowed to receive rescue laxative(s) as needed regardless of being on a stable laxative regimen at baseline (apart from within 24 hours of the start of the Treatment Period).
In studies V9222 and V9236, OIC was confirmed through a 2-week run-in period and was defined as ≤5 SBMs during the 14 consecutive days prior to the randomisation and ≥1 of the following bowel symptoms in ≥25% of all BMs regardless of the use of rescue laxatives: presence of straining during bowel movement, feeling of incomplete evacuation, passage of hard stools or small pellets.
In studies V9222 and V9236, the mean age of the subjects was 64.3 years; 51.8% were 65 years of age or older; 39.4% were women and 97.1% were Japanese.
Naldemedine 200 micrograms or placebo was administered for 2 weeks to cancer patients with OIC. The primary endpoint for Study V9236 and the secondary endpoint, without multiplicity adjustment, for Study V9222 were the proportion of SBM responders during the 2-week Treatment Period. A responder was defined as a patient with ≥3 frequency of SBMs per week and an increase from baseline ≥1 SBM per week during the 2-week Treatment Period.
Table 5. Proportion of SBM responders in patients with cancer and OIC during the 2-week treatment period (Studies V9222 and V9236):
| V9222 | V9236 | |||||
|---|---|---|---|---|---|---|
| Naldemedine (N=58) | Placebo (N=56) | Treatment Difference [95% Cl] | Naldemedine (N=97) | Placebo (N=96) | Treatment Difference [95% Cl] | |
| Patients responding, n(%) | 45 (77.6%) | 21 (37.5%) | 40.1% [23.5%, 56.7%] | 69 (71.1%) | 33 (34.4%) | 36.8% [23.7%, 49.9%] |
| p value* | <0.0001 | <0.0001 | ||||
* Statistically significant: p-values based on the Chi-square test.
The European Medicines Agency has deferred the obligation to submit the results of studies with Rizmoic in one or more subsets of the paediatric population in the treatment of opioid-induced constipation (see section 4.2 for information on paediatric use).
Naldemedine is absorbed with a time to achieve peak plasma concentration of approximately 0.75 hours in the fasted state. The absolute bioavailability of naldemedine has not been established. The absolute bioavailability of naldemedine is estimated to be in the range of 20% to 56%.
There is no clinically significant food effect. The peak plasma concentration was reduced by 35% and time to achieve peak plasma concentration was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, whereas no significant difference was observed in the area under the plasma concentration-time curve by food intake. Based on these data, naldemedine can be taken with or without food (see section 4.2).
Naldemedine is highly bound to serum proteins, predominantly to human serum albumin and to a lesser extent to α1-acid-glycoprotein and γ-globulin, with a mean protein binding ratio in humans of 93.2%. The apparent volume of distribution is approximately 155 litres.
Naldemedine is primarily metabolized by CYP3A to nor-naldemedine, with a minor contribution from UGT1A3 to form naldemedine 3-G.
Following oral administration of [14C]-labelled naldemedine, the primary metabolite in plasma was nor-naldemedine, with a relative exposure compared to naldemedine of approximately 9 to 13%. Naldemedine 3-G was a minor metabolite in plasma, with a relative exposure to naldemedine of less than 3%.
Naldemedine also undergoes cleavage in the gastrointestinal tract to form benzamidine and naldemedine carboxylic acid.
In in vitro studies at clinically relevant concentrations, naldemedine did not inhibit the major CYP enzymes (including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, or CYP4A11 isozymes) and is not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, BCRP, P-gp, MATE1, MATE2-K or BSEP transporters. Naldemedine did not cause significant induction of CYP1A2, CYP2B6 or CYP3A4 isozymes. Therefore, treatment with naldemedine is not expected to alter the pharmacokinetics of co-administered medicines that are substrates of these enzymes and transporters.
The apparent terminal elimination half-life of naldemedine is approximately 11 hours, and the apparent total clearance (CL/F) of naldemedine is 8.4 L/h. Following oral administration of radiolabelled naldemedine, 57.3% and 34.8% of the dose was excreted in urine and faeces for the [oxadiazole-14C] - naldemedine and 20.4% and 64.3% of the dose was excreted as the [carbonyl-14C] - naldemedine in urine and faeces, respectively. Approximately 20% of the naldemedine dose is excreted unchanged in urine.
The peak plasma concentration and area under the plasma concentration-time curve increased in an almost dose-proportional manner within the dose range of 0.1 to 100 mg. A slight accumulation (1 to 1.3-fold) for peak plasma concentration and area under the plasma concentration–time curve was observed after once daily multiple dose administration in the fasted state for 10 days.
Age, gender, body weight and race A population pharmacokinetic analysis from clinical studies with naldemedine did not identify a clinically meaningful effect of age, gender, body weight or race on the pharmacokinetics of naldemedine.
The pharmacokinetics of naldemedine in the paediatric population has not been studied (see section 4.2).
The pharmacokinetics of naldemedine after administration of a single 200 microgram dose of naldemedine was studied in subjects with mild, moderate or severe renal impairment, or with endstage renal disease (ESRD) requiring haemodialysis, and compared with healthy subjects with normal renal function.
The pharmacokinetics of naldemedine between subjects with mild, moderate or severe renal impairment, or subjects with ESRD requiring hemodialysis and healthy subjects with normal renal function were similar.
Plasma concentrations of naldemedine in subjects with ESRD requiring dialysis were similar when naldemedine was administered either pre- or post-haemodialysis, indicating that naldemedine was not removed from the blood by haemodialysis.
The effect of hepatic impairment on the pharmacokinetics of a single 200 microgram dose of naldemedine was studied in subjects with hepatic impairment classified as mild (Child-Pugh class A) or moderate (Child-Pugh class B) and compared with healthy subjects with normal hepatic function. The pharmacokinetics of naldemedine between subjects with mild or moderate hepatic impairment and healthy subjects with normal hepatic function were similar. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naldemedine was not evaluated.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and embryo-fetal development.
In the rat fertility and early embryonic development study, prolongation of the dioestrous phase was observed at 10 mg/kg/day and above, but was not observed at 1 mg/kg/day (12 times the exposure [AUC0-24hr] in humans at an oral dose of 200 micrograms). The effect on oestrous cycle is not considered clinically relevant at the proposed therapeutic dose. No adverse effects were observed in male or female fertility and reproductive performance at up to 1000 mg/kg/day (in excess of 16,000 times the exposure [AUC0-24hr] in humans at an oral dose of 200 micrograms).
In the pre- and postnatal development study in rats, one dam died at parturition at 1000 mg/kg/day, and poor nursing, suppression of body weight gain and decrease in food consumption were noted at 30 and 1000 mg/kg/day. Decreases in the viability index on Day 4 after birth were noted at 30 and 1000 mg/kg/day and low body weights and delayed pinna unfolding were noted at 1000 mg/kg/day in pups. There was no adverse effect on pre- and postnatal development at 1 mg/kg/day (12 times the exposure [AUC0-24hr] in humans at an oral dose of 200 micrograms).
Placental transfer of [carbonyl-14C]-naldemedine-derived radioactivity was observed in pregnant rats. [Carbonyl-14C]-naldemedine-derived radioactivity was excreted into milk in lactating rats.
In juvenile toxicity studies in rats, at the same dose levels, exposure in juvenile animals (PND 10) was increased compared to adult animals (2.3 to 7.4-fold). Novel histopathology findings were observed at all doses tested in female rats in ovaries (tertiary follicles/luteal cysts) in addition to irregular oestrous cycles, hyperplasia of mammary gland, and vaginal mucification already observed in adult animals (the lowest dose tested corresponded to an exposure margin of 6 or more, depending on the age of the pups). Three-day earlier vaginal opening indicative of an early onset of sexual maturity was also observed, but only at high exposures considered sufficiently in excess of the maximum human exposure at an oral dose of 200 micrograms.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
