Leaflet RIZMOIC 200mcg film-coated tablets
Indicated for: constipation
Route of administration: oral
Substance: naldemedine (laxative)
ATC: A06AH05 (Alimentary tract and metabolism | Drugs for constipation | Peripheral opioid receptor antagonists)
This medicine may change blood electrolyte levels.
Naldemedine is a medicine used in adults to treat constipation caused by opioid pain medicines, usually when laxatives have not worked well enough. Opioids relieve pain but can slow bowel movement; naldemedine mainly blocks this opioid effect in the gut, so it helps restore bowel activity without usually reducing pain control.
It is taken by mouth, generally as one tablet once daily, at about the same time each day, with or without food. Do not change your opioid dose or stop your pain medicine on your own. Tell your doctor or pharmacist about all other medicines you use, especially antibiotics, antifungals, seizure medicines, rifampicin, and herbal products such as St John’s wort.
Common side effects include stomach pain, diarrhoea, nausea, vomiting, and general abdominal discomfort. Seek medical advice if diarrhoea is severe or persistent, or if you develop strong cramps, sweating, chills, anxiety, irritability, or new pain, as these may point to dehydration, opioid withdrawal, or an intestinal problem.
Naldemedine should not be used if bowel blockage is known or suspected and needs caution in people with serious digestive disease. Tell your healthcare team if you are pregnant, breastfeeding, have significant liver disease, or have ongoing abdominal pain. Treatment should be monitored to improve bowel function safely.
General data about RIZMOIC 200mcg
- Substance: naldemedine
- Date of latest medicines list: 01-03-2026
- Product code: W71727001
- Concentration: 200mcg
- Pharmaceutical form: film-coated tablets
- Quantity: 30
- Product type: Original
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Leaflet RIZMOIC 200mcg
Contents of the package leaflet for the medicine RIZMOIC 200mcg film-coated tablets
1. NAME OF THE MEDICINAL PRODUCT
Rizmoic 200 micrograms film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200 micrograms naldemedine (as tosylate).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Round, approximately 6.5 mm diameter, yellow tablet debossed with '222' and Shionogi logo on oneside and '0.2' on the other side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Rizmoic is indicated for the treatment of opioid-induced constipation (OIC) in adult patients who havepreviously been treated with a laxative.
4.2 Posology and method of administration
The recommended dose of naldemedine is 200 micrograms (one tablet) daily.
Rizmoic may be used with or without laxative(s). It may be taken at any time of the day but it isrecommended to be taken at the same time every day.
Alteration of the analgesic dosing regimen prior to initiating Rizmoic is not required.
Rizmoic must be discontinued if treatment with the opioid pain medicinal product is discontinued.
Special populationsElderly
No dose adjustment is required in patients older than 65 years of age (see section 5.2).
Due to the limited therapeutic experience in patients 75 years old and older, naldemedine therapyshould be initiated with caution in this age group.
Renal impairmentNo dose adjustment is required in patients with renal impairment (see section 5.2).
Due to the limited therapeutic experience, patients with severe renal impairment should be clinicallymonitored when initiating therapy with naldemedine (see section 4.4).
Hepatic impairmentNo dose adjustment is required in patients with mild or moderate hepatic impairment.
Use in patients with severe hepatic impairment is not recommended (see sections 4.4 and 5.2).
Paediatric populationThe safety and efficacy of naldemedine in children and adolescents aged below 18 years have not yetbeen established. No data are available.
Method of administrationOral use.
Rizmoic should be taken once daily, with or without food (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with known or suspected gastrointestinal obstruction or perforation or patients at increasedrisk of recurrent obstruction, due to the potential for gastrointestinal perforation (see section 4.4).
4.4 Special warnings and precautions for use
Gastrointestinal perforation
Cases of gastrointestinal perforation have been reported in the post-marketing setting (see section 4.8),including fatal cases, when naldemedine was used in patients who were at an increased risk ofgastrointestinal (GI) perforation, (e.g. diverticular disease and underlying malignancies of thegastrointestinal tract or peritoneal metastases).
Naldemedine must not be used in patients with known or suspected GI obstruction or in patients atincreased risk of recurrent obstruction, due to the potential for GI perforation (see section 4.3).
Caution with regards to the use of naldemedine should be exercised in patients with anyconditions which might result in impaired integrity of the gastrointestinal tract wall (e.g. peptic ulcerdisease, Ogilvie’s syndrome, malignancy of the GI tract, Crohn’s disease). The overall benefit risk foreach patient should be taken into account. Patients should be monitored for the development of severe,persistent or worsening abdominal pain. If obstruction or perforation are suspected, naldemedine mustbe discontinued (see section 4.3).
Gastrointestinal adverse reactionsAbdominal adverse reactions (e.g. abdominal pain, vomiting and diarrhoea) have been reported with
Rizmoic. Patients should be advised to report severe, persistent or worsening symptoms to theirphysician. In cases of severe diarrhoea or abdominal pain, the patient should be monitored and treatedfor dehydration using rehydration and appropriate treatment as needed (see section 4.8).
Opioid withdrawal syndrome
Opioid withdrawal syndrome is a cluster of three or more of the following signs or symptoms:
dysphoric mood, nausea or vomiting, muscle aches, lacrimation or rhinorrhea, pupillary dilation orpiloerection or sweating, diarrhoea, yawning, fever or insomnia. Opioid withdrawal syndrometypically develops within minutes to several days following administration of an opioid antagonist.
Caution should be exercised with regards to opioid withdrawal. Patients should be advised todiscontinue naldemedine and to contact their physician if opioid withdrawal occurs. Cases of possibleopioid withdrawal syndrome have been reported in the naldemedine clinical programme (seesection 4.8).
Patients having disruptions to the blood-brain barrier (e.g., primary brain malignancies, centralnervous system (CNS) metastases or other inflammatory conditions, active multiple sclerosis andadvanced Alzheimer’s disease) may be at increased risk of opioid withdrawal or reduced analgesia.
The overall benefit-risk of naldemedine should be considered in these patients with close monitoringfor symptoms of opioid withdrawal.
Patients with cardiovascular conditions
Naldemedine was not studied in the clinical trial programme in patients who had a recent history ofmyocardial infarction, stroke or transient ischaemic attack within 3 months of screening. Thesepatients should be clinically monitored when taking Rizmoic.
A QTc study performed with naldemedine in healthy volunteers did not indicate any prolongation ofthe QT interval. Patients with cardiovascular disease risk factors were not excluded from thenaldemedine clinical trial programme, with BMI ≥ 30 kg/m2, and a medical history of hypertensionand/or dyslipidaemia being the most commonly reported risk factors.
Severe renal impairmentDue to limited therapeutic experience in patients with severe renal impairment, these patients shouldbe clinically monitored when initiating therapy with naldemedine (see section 4.2).
Severe hepatic impairmentNaldemedine has not been studied in patients with severe hepatic impairment. The use of naldemedineis not recommended in these patients (see section 4.2).
Opioid pain medicinal products
There is limited experience in patients treated with opioid pain medicinal product(s) at daily doses ofmore than the equivalent of 400 mg of morphine. There is no experience in patients treated forconstipation induced by partial opioid mu-agonists (e.g. buprenorphine).
Caution should be exercised when treating these patients.
Concomitant use with strong CYP3A inhibitors and inducers
Concomitant use of naldemedine with strong CYP3A inhibitors (e.g. grapefruit juice, itraconazole,ketoconazole, ritonavir, indinavir, saquinavir, telithromycin and clarithromycin) leads to an increase innaldemedine exposure and may increase the risk of adverse reactions. Concomitant use with strong
CYP3A inhibitors should be avoided.
Concomitant use of naldemedine with strong CYP3A inducers (e.g. St. John’s wort (Hypericumperforatum), rifampicin, carbamazepine, phenobarbital and phenytoin) leads to a decrease innaldemedine exposure and may reduce the efficacy of naldemedine. Concomitant use with strong
CYP3A inducers is not recommended (see section 4.5). Concomitant use of naldemedine withmoderate CYP3A inducers (e.g. efavirenz) has not been established and should be used with caution(see section 4.5).
SodiumThis medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on naldemedine
Naldemedine is primarily metabolised by CYP3A with some contribution from UGT1A3 and is asubstrate of P-glycoprotein (P-gp) (see section 5.2).
Interactions with CYP3A inhibitors
Itraconazole, a strong CYP3A inhibitor, increased exposure to naldemedine 2.9 fold that may result inan increased risk of adverse reactions.
Concomitant use of strong CYP3A inhibitors such as grapefruit juice, itraconazole, ketoconazole,ritonavir, indinavir, saquinavir, telithromycin and clarithromycin should be avoided. If use with strong
CYP3A inhibitors is unavoidable, monitor for adverse reactions (see section 4.4).
Concomitant use of moderate CYP3A inhibitors such as fluconazole, may increase the plasmaconcentration of naldemedine. If used with moderate CYP3A inhibitors, monitor for adverse reactions.
There is no risk of interaction with concomitant use of mild CYP3A inhibitors.
Interaction with strong and moderate CYP3A inducers
Rifampicin, a strong CYP3A inducer, significantly decreased exposure to naldemedine by 83% .
Concomitant use of strong CYP3A inducers such as St. John’s wort (Hypericum perforatum),rifampicin, carbamazepine, phenobarbital and phenytoin is not recommended. Concomitant use ofnaldemedine with moderate inducers (e.g. efavirenz) has not been established, and patients should bemonitored (see section 4.4).
Interaction with strong P-gp inhibitors
Concomitant use of P-gp inhibitors such as cyclosporine may increase plasma concentrations ofnaldemedine. If naldemedine is used with strong P-gp inhibitors, monitor for adverse reactions.
4.6 Fertility, pregnancy and lactation
There are no data from the use of naldemedine in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).
The use of naldemedine during pregnancy may precipitate opioid withdrawal in a fetus due to theimmature fetal blood brain barrier.
Naldemedine should not be used during pregnancy unless the clinical condition of the woman requirestreatment with naldemedine.
Breast-feedingIt is unknown whether naldemedine/metabolites are excreted in human milk. Available data in ratshave shown excretion of naldemedine in milk (see section 5.3).
At therapeutic doses, most opioids (e.g morphine, meperidine, methadone) are excreted into breastmilk in minimal amounts. There is a theoretical possibility that naldemedine provokes opioidwithdrawal in a breast-fed neonate whose mother is taking an opioid receptor agonist.
A risk to the suckling child cannot be excluded.
Naldemedine should not be used during breast-feeding.
FertilityNo human data on the effect of naldemedine on fertility are available. Naldemedine was found to haveno clinically relevant adverse effects on fertility or reproductive performance in male and female rats(see section 5.3).
4.7 Effects on ability to drive and use machines
Naldemedine has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The most commonly reported adverse reactions in patients with chronic non-cancer pain and OIC wereabdominal pain (7.8%), diarrhoea (5.9%), nausea (3.6%), and vomiting (1.1%). The majority of thesegastrointestinal adverse reactions were of mild to moderate severity and resolved withoutdiscontinuation of naldemedine treatment. One serious case of abdominal pain and one serious case ofnausea were reported in patients with chronic non-cancer pain and OIC.
The most commonly reported adverse reactions in patients with cancer and OIC were diarrhoea(24.5%) and abdominal pain (3.9%). The majority of these gastrointestinal adverse reactions were ofmild to moderate severity and resolved with treatment. Two serious cases of diarrhoea were reportedin patients with cancer and OIC.
Tabulated list of adverse reactionsThe adverse reactions with naldemedine 200 microgram tablets in patients with chronic non-cancerpain and OIC and in patients with cancer and OIC reported in clinical studies are presented in thetables according to the MedDRA system organ classification. The frequency categories are definedusing the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) and not known(frequency cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.
Table 1. Adverse reactions presented by System Organ Class and frequency inpatients with chronic non-cancer pain and opioid-induced constipation
System organ Common Uncommon Rare Unknownclass
Immune system Hypersensitivityadisorders
Gastrointestinal Diarrhoea Gastrointestinaldisorders Abdominal painb perforation
Nausea
VomitingGeneral disorders Opioidand withdrawaladministration syndromesite conditionsaOne serious report of hypersensitivity reaction was observed in clinical studies withnaldemedine. The patient recovered following discontinuation from the studybMedDRA Preferred Terms: abdominal pain, abdominal pain upper, abdominal pain lower andabdominal discomfort
Table 2. Adverse reactions presented by System Organ Class and frequency inpatients with cancer and opioid-induced constipation
System organ Very Common Common Uncommon Unknownclass
Gastrointestinal Diarrhoea Abdominal paina Gastrointestinaldisorders perforation
General disorders Opioidand withdrawaladministration syndromesite conditionsaMedDRA Preferred Terms: abdominal pain, abdominal pain upper, abdominal pain lower andabdominal discomfort
Description of selected adverse reactionsOpioid withdrawal syndrome
Possible opioid withdrawal, defined as at least three adverse reactions potentially related to opioidwithdrawal that occurred on the same day and that were not exclusively related to the gastrointestinalsystem, occurred in 0.8% (9/1 163) of patients with chronic non-cancer pain and OIC takingnaldemedine compared to 0.2% (2/1 165) of patients taking placebo regardless of maintenance opioidtreatment, and 0.6% (1/155) of patients with cancer and OIC taking naldemedine 200 microgramscompared to 0% (0/152) of patients taking placebo. Symptoms included, but were not limited tohyperhidrosis, chills, lacrimation increased, hot flush/flushing, pyrexia, sneezing, feeling cold,abdominal pain, diarrhoea, nausea, vomiting, arthralgia, myalgia, and tachycardia (see section 4.4).
Gastrointestinal disordersAbdominal pain, diarrhoea, nausea and vomiting were the most commonly reported adverse reactionsin clinical studies with patients with chronic non-cancer pain and OIC and with patients with cancerand OIC. The majority of these gastrointestinal adverse reactions were mild to moderate severity andresolved with treatment. The discontinuation rate due to gastrointestinal treatment emergent adverseevents with naldemedine 200 micrograms compared to placebo was 3.2% and 1% respectively inpatients with chronic non-cancer pain and OIC and 4.5% and 0% respectively for patients with cancerand OIC.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
Healthy volunteers
A single dose of naldemedine up to 100 mg and multiple doses of up to 30 mg/day for 10 days wereadministered to healthy volunteers in clinical studies. Dose-dependent increases ingastrointestinal-related adverse reactions, including abdominal pain, diarrhoea, and nausea, wereobserved. These were mild or moderate in severity and resolved.
Patients with OIC
A single dose of naldemedine (0.01 mg to 3 mg) and multiple doses of 0.4 mg/day have beenadministered to patients with OIC in clinical studies. A patient who took a single dose of naldemedine1 mg experienced severe opioid withdrawal syndrome, including nausea and stomach cramping andwas given esomeprazole and ondansetron for nausea and midazolam hydrochloride for stomachcramping. The symptoms resolved. In clinical studies, patients with OIC who were administered0.4 mg/day (twice the recommended dose) over 4 weeks had an increased incidence of GI-relatedadverse drug reactions including diarrhoea and abdominal pain frequently within 1-2 days after initialdosing.
ManagementThere is no specific antidote for naldemedine. Naldemedine is not removed from the body byhaemodialysis. In the event of an overdose, patients should be closely monitored for potential signsand symptoms of opioid withdrawal syndrome (see section 4.4) and provided with appropriatesupportive care.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for constipation, peripheral opioid receptor antagonists, ATC code:
A06AH05.
Mechanism of actionNaldemedine 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 thegastrointestinal tract, thereby decreasing the constipating effects of opioids without reversing thecentral nervous system (CNS)-mediated opioid effects.
Naldemedine is a derivative of naltrexone to which a side chain has been added that increases themolecular weight and the polar surface area, thereby reducing its ability to cross the blood-brainbarrier (BBB); the CNS penetration of naldemedine is expected to be negligible at the recommendeddose. Additionally, naldemedine is a substrate of the P-glycoprotein (P-gp) efflux transporter, whichmay also be involved in reducing naldemedine penetration into the CNS. Based on this, naldemedineis expected to exert its anti-constipating effects on opioids without reversing their CNS-mediatedanalgesic effects.
Clinical efficacy and safetyThe efficacy and safety of naldemedine has been established in patients with chronic non-cancer painand OIC and in patients with cancer and OIC.
Clinical studies in patients with chronic non-cancer pain and OIC
The safety and efficacy of naldemedine was evaluated in two identical, 12-week randomised, double-blind placebo-controlled trials (Studies V9231 and V9232) in which naldemedine was used withoutlaxatives 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 non-cancer pain and OIC.
Patients receiving a stable opioid morphine equivalent daily dose of ≥ 30 mg for at least 4 weeksbefore 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 asno more than 4 spontaneous bowel movements (SBMs) total over 14 consecutive days and <3 SBMsin a given week with at least 25% of the SBMs associated with one or more of the followingconditions: (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 confirmedthrough a 2-week run-in period and was defined as no more than 4 SBMs total over 14 consecutivedays and <3 SBMs in a given week.
A SBM was defined as a bowel movement (BM) without rescue laxative taken within the past24 hours.
In studies V9231 and V9232, patients had to either not be using laxatives or be willing to discontinuelaxative use at the time of Screening and be willing to use only the provided rescue laxatives duringthe Screening and Treatment Periods. All study participants took laxatives previously for the treatmentof OIC. In study V9235, patients on a stable laxative regimen at screening (52.4%) were allowed tocontinue using that same regimen without change throughout the study duration. In the run-in andtreatment 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 notenrolled in these studies.
A total of 547 patients in study V9231, 551 patients in study V9232 and 1246 patients in study V9235were randomised in a 1:1 ratio to receive 200 micrograms of naldemedine or placebo once daily for12 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 was53.2 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%) andosteoarthritis (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 patientswho participated in studies V9231, V9232 and V9235 were taking a wide range of opioids.
The mean baseline opioid morphine equivalent daily dose was 132.42 mg, 120.93 mg, and 122.06 mgper 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, definedas: ≥3 SBMs per week and a change from baseline of ≥1 SBM per week for at least 9 out of the12 study weeks and 3 out of the last 4 weeks. The primary efficacy endpoint for study V9235 was thechange 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 theprimary 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 Placebo Naldemedine Placebo(N=273) (N=272) (N=276) (N=274)
Proportion of SBM Responders 47.6% 34.6% 52.5% 33.6%
Treatment difference 13.0% 18.9%(95% CI: 4.8%, 21.3%, (95% CI: 10.8%, 27.0%,p=0.0020*) p<0.0001*)
Change in frequency of SBMs perweek (LS Mean)
From baseline to the last 2 weeks of3.42 2.12 3.56 2.16treatment**
From baseline to week 1** 3.48 1.36 3.86 1.69
Change in frequency of CSBMsper week (LS Mean)
From baseline to the last 2 weeks of2.58 1.57 2.77 1.62treatment**
V9231 V9232
Naldemedine Placebo Naldemedine Placebo(N=273) (N=272) (N=276) (N=274)
Change in frequency of SBMswithout straining per week (LS
Mean)
From baseline to the last 2 weeks of1.46 0.73 1.85 1.10treatment***
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 thefrequency of BMs as presented in Table 4.
Table 4. Change in the frequency of BMs per week from baseline to each visit (LS Mean) ITTpopulation in study V9235
Naldemedine Placebo(N=621) (N=620)
Mean frequency of BMs at 2.02 2.02baseline
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-LIRsubgroups.
In studies V9231 and V9232, patients who, based on concomitant medication records, were onlaxative 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 receivedrescue laxative at or after screening were considered non-LIR. The number of patients in the LIR andnon-LIR subgroups were 629 (naldemedine: 317 and placebo: 312) and 451 (naldemedine: 223 andplacebo: 228) for pooled Studies V9231 and V9232. All study participants took previous laxatives atsome 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 statisticallysignificant (p<0.0001).
In the non-LIR subgroup, consistent with the results in the LIR subgroup, a greater proportion ofresponders was observed with naldemedine (54.3%) compared with placebo (38.9%) and thedifference 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 frombaseline, assessed as a secondary endpoint, showed that subjects in the naldemedine group hadimprovements in the frequency of BMs compared with subjects in the placebo group in both LIR (3.10vs 1.90, p=0.0210) and non-LIR (4.26 vs 3.39, p=0.1349) subgroups.
Clinical studies in patients with cancer and OIC
The safety and efficacy of naldemedine was also evaluated in 2 randomised, double-blind and placebo-controlled 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 bereceiving a stable dose. The studies included a 2-week screening period, 2-week treatment period and4-week follow-up period. For patients receiving laxative therapy at the screening visit, it had to becontinued at a stable dose until the end of the treatment period. Patients were allowed to receive rescuelaxative(s) as needed regardless of being on a stable laxative regimen at baseline (apart from within24 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 bowelsymptoms in ≥25% of all BMs regardless of the use of rescue laxatives: presence of straining duringbowel 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 ageor 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. Aresponder 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-weektreatment period (Studies V9222 and V9236)
V9222 V9236
Treatment Treatment
Naldemedine Placebo Naldemedine Placebo
Difference Difference(N=58) (N=56) (N=97) (N=96)[95% Cl] [95% Cl]
Patients 40.1% 36.8%responding, 45 (77.6%) 21 (37.5%) [23.5%, 69 (71.1%) 33 (34.4%) [23.7%,n (%) 56.7%] 49.9%]p value* <0.0001 <0.0001
*Statistically significant: p-values based on the Chi-square test.
Paediatric populationThe 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-inducedconstipation (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Naldemedine is absorbed with a time to achieve peak plasma concentration of approximately0.75 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% andtime to achieve peak plasma concentration was delayed from 0.75 hours in the fasted state to 2.5 hoursin the fed state, whereas no significant difference was observed in the area under the plasmaconcentration-time curve by food intake. Based on these data, naldemedine can be taken with orwithout food (see section 4.2).
DistributionNaldemedine is highly bound to serum proteins, predominantly to human serum albumin and to alesser extent to α1-acid-glycoprotein and γ-globulin, with a mean protein binding ratio in humans of93.2%. The apparent volume of distribution is approximately 155 litres.
BiotransformationNaldemedine is primarily metabolised 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 wasnor-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 lessthan 3%.
Naldemedine also undergoes cleavage in the gastrointestinal tract to form benzamidine andnaldemedine carboxylic acid.
In in vitro studies at clinically relevant concentrations, naldemedine did not inhibit the major CYPenzymes (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 notcause significant induction of CYP1A2, CYP2B6 or CYP3A4 isozymes. Therefore, treatment withnaldemedine is not expected to alter the pharmacokinetics of co-administered medicines that aresubstrates of these enzymes and transporters.
EliminationThe apparent terminal elimination half-life of naldemedine is approximately 11 hours, and theapparent total clearance (CL/F) of naldemedine is 8.4 L/h. Following oral administration of radio-labelled 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 isexcreted unchanged in urine.
Linearity/non-linearityThe peak plasma concentration and area under the plasma concentration-time curve increased in analmost 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 wasobserved after once daily multiple dose administration in the fasted state for 10 days.
Pharmacokinetics in subpopulations
Age, gender, body weight and race
A population pharmacokinetic analysis from clinical studies with naldemedine did not identify aclinically meaningful effect of age, gender, body weight or race on the pharmacokinetics ofnaldemedine.
The pharmacokinetics of naldemedine in the paediatric population has not been studied (seesection 4.2).
Renal impairmentThe pharmacokinetics of naldemedine after administration of a single 200 microgram dose ofnaldemedine was studied in subjects with mild, moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring haemodialysis, and compared with healthy subjects with normalrenal function.
The pharmacokinetics of naldemedine between subjects with mild, moderate or severe renalimpairment, or subjects with ESRD requiring hemodialysis and healthy subjects with normal renalfunction were similar.
Plasma concentrations of naldemedine in subjects with ESRD requiring dialysis were similar whennaldemedine was administered either pre- or post-haemodialysis, indicating that naldemedine was notremoved from the blood by haemodialysis.
Hepatic impairmentThe effect of hepatic impairment on the pharmacokinetics of a single 200 microgram dose ofnaldemedine 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 andhealthy 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.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and embryo-fetaldevelopment.
In the rat fertility and early embryonic development study, prolongation of the dioestrous phase wasobserved 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 notconsidered clinically relevant at the proposed therapeutic dose. No adverse effects were observed inmale or female fertility and reproductive performance at up to 1000 mg/kg/day (in excess of16,000 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 at30 and 1000 mg/kg/day. Decreases in the viability index on Day 4 after birth were noted at 30 and1000 mg/kg/day and low body weights and delayed pinna unfolding were noted at 1000 mg/kg/day inpups. There was no adverse effect on pre- and postnatal development at 1 mg/kg/day (12 times theexposure [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) wasincreased compared to adult animals (2.3 to 7.4-fold). Novel histopathology findings were observed atall doses tested in female rats in ovaries (tertiary follicles/luteal cysts) in addition to irregular oestrouscycles, 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 thepups). Three-day earlier vaginal opening indicative of an early onset of sexual maturity was alsoobserved, but only at high exposures considered sufficiently in excess of the maximum humanexposure at an oral dose of 200 micrograms.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol
Croscarmellose sodium
Magnesium stearate
Film coatingHypromellose
Talc
Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium/aluminium blister containing 7, 10 or 14 film-coated tablets.
Pack sizes of 7, 10, 28, 30, 84 or 100 film-coated tablets.
The medicine is available in aluminium unit dose blisters, containing 10 tablets.
Pack sizes of 30 x 1 tablets in unit dose blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European
Medicines Agency http://www.ema.europa.eu.