Rizmoic

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 

  



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

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 one 

side 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 have 

previously been treated with a laxative. 

 

4.2 Posology and method of administration 

 

Posology 

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 is 

recommended 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 populations 

Elderly patients 

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 therapy 

should be initiated with caution in this age group. 

 

Renal impairment 

No 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 clinically 

monitored when initiating therapy with naldemedine. 

 

Hepatic impairment 

No 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). 

 



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Opioid pain medicinal products 

There is limited experience in patients treated with opioid pain medicinal product(s) at daily doses of 

more than the equivalent of 400 mg of morphine. There is no experience in patients treated for 

constipation induced by partial opioid mu-agonists (e.g. buprenorphine). 

 

Paediatric population 

The safety and efficacy of naldemedine in children and adolescents aged below 18 years have not yet 

been established. No data are available. 

 

Method of administration 

Oral 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 increased 

risk 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, including fatal 

cases, when naldemedine was used in patients who were at an increased risk of gastrointestinal (GI) 

perforation, (e.g. diverticular disease and underlying malignancies of the gastrointestinal tract or 

peritoneal metastases). 

Naldemedine must not be used in patients with known or suspected GI obstruction or in patients at 

increased 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 any 

conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g. peptic ulcer 

disease, Ogilvie’s syndrome, malignancy of the GI tract, Crohn’s disease). The overall benefit risk for 
each 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 must 

be discontinued (see section 4.3). 

 

Gastrointestinal adverse reactions 

Abdominal 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 their 

physician. In cases of severe diarrhoea or abdominal pain, the patient should be monitored and treated 

for 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 or 

piloerection or sweating, diarrhoea, yawning, fever or insomnia. Opioid withdrawal syndrome 

typically 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 to 

discontinue naldemedine and to contact their physician if opioid withdrawal occurs. Cases of possible 

opioid withdrawal syndrome have been reported in the naldemedine clinical programme (see 

section 4.8). 

 

Patients having disruptions to the blood-brain barrier (e.g., primary brain malignancies, central 

nervous system (CNS) metastases or other inflammatory conditions, active multiple sclerosis and 

advanced 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 monitoring 

for symptoms of opioid withdrawal. 



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Patients with cardiovascular conditions 

Naldemedine was not studied in the clinical trial programme in patients who had a recent history of 

myocardial infarction, stroke or transient ischaemic attack within 3 months of screening. These 

patients should be clinically monitored when taking Rizmoic. 

A QTc study performed with naldemedine in healthy volunteers did not indicate any prolongation of 

the QT interval. Patients with cardiovascular disease risk factors were not excluded from the 

naldemedine clinical trial programme, with BMI ≥ 30 kg/m2, and a medical history of hypertension 
and/or dyslipidaemia being the most commonly reported risk factors. 

 

Severe hepatic impairment 

Naldemedine has not been studied in patients with severe hepatic impairment. The use of naldemedine 

is not recommended in these patients (see section 4.2). 

 

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 in 

naldemedine 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 (Hypericum 
perforatum), rifampicin, carbamazepine, phenobarbital and phenytoin) leads to a decrease in 

naldemedine 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 with 

moderate CYP3A inducers (e.g. efavirenz) has not been established and should be used with caution 

(see section 4.5). 

 

Sodium 

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, and is therefore 

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 a 

substrate 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 in 

an 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 plasma 

concentration 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 of 

naldemedine with moderate inducers (e.g. efavirenz) has not been established, and patients should be 

monitored (see section 4.4). 

 

Interaction with strong P-gp inhibitors 

Concomitant use of P-gp inhibitors such as cyclosporine may increase plasma concentrations of 

naldemedine. If naldemedine is used with strong P-gp inhibitors, monitor for adverse reactions. 



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4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

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 the 

immature fetal blood brain barrier. 

Naldemedine should not be used during pregnancy unless the clinical condition of the woman requires 

treatment with naldemedine. 

 

Breast-feeding 

It is unknown whether naldemedine/metabolites are excreted in human milk. Available data in rats 

have shown excretion of naldemedine in milk (see section 5.3).  

At therapeutic doses, most opioids (e.g morphine, meperidine, methadone) are excreted into breast 

milk in minimal amounts. There is a theoretical possibility that naldemedine provokes opioid 

withdrawal 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. 

 

Fertility 

No human data on the effect of naldemedine on fertility are available. Naldemedine was found to have 

no 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 

 

Summary of the safety profile 

The most commonly reported adverse reactions in patients with chronic non-cancer pain and OIC were 

abdominal pain (7.8%), diarrhoea (5.9%), nausea (3.6%), and vomiting (1.1%). The majority of these 

gastrointestinal adverse reactions were of mild to moderate severity and resolved without 

discontinuation of naldemedine treatment. One serious case of abdominal pain and one serious case of 

nausea 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 of 

mild to moderate severity and resolved with treatment. Two serious cases of diarrhoea were reported 

in patients with cancer and OIC. 

 

Tabulated list of adverse reactions 

The adverse reactions with naldemedine 200 microgram tablets in patients with chronic non-cancer 

pain and OIC and in patients with cancer and OIC reported in clinical studies are presented in the 

tables according to the MedDRA system organ classification. The frequency categories are defined 

using 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, adverse 

reactions are presented in order of decreasing seriousness. 

 



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Table 1. Adverse reactions presented by System Organ Class and frequency in 

patients with chronic non-cancer pain and opioid-induced constipation 

 

System Organ 

Class 

Common Uncommon Rare Unknown 

Immune system 

disorders 

  Hypersensitivity
a
  

Gastrointestinal 

disorders 

Diarrhoea 

Abdominal pain
b
 

Nausea 

Vomiting 

  Gastrointestinal 

perforation 

General disorders 

and 

administration 

site conditions 

 Opioid 

withdrawal 

syndrome 

  

a
One serious report of hypersensitivity reaction was observed in clinical studies with 

naldemedine. The patient recovered following discontinuation from the study 

b
MedDRA Preferred Terms: abdominal pain, abdominal pain upper, abdominal pain lower and 

abdominal discomfort 

 

Table 2. Adverse reactions presented by System Organ Class and frequency in 

patients with cancer and opioid-induced constipation 

 

System Organ 

Class 

Very Common Common Uncommon Unknown 

Gastrointestinal 

disorders 

Diarrhoea 

 

Abdominal pain
a
   Gastrointestinal 

perforation 

General disorders 

and 

administration 

site conditions 

  Opioid 

withdrawal 

syndrome 

 

a
MedDRA Preferred Terms: abdominal pain, abdominal pain upper, abdominal pain lower and 

abdominal discomfort 

 

Description of selected adverse reactions 

Opioid withdrawal syndrome 

Possible opioid withdrawal, defined as at least three adverse reactions potentially related to opioid 

withdrawal that occurred on the same day and that were not exclusively related to the gastrointestinal 

system, occurred in 0.8% (9/1,163) of patients with chronic non-cancer pain and OIC taking 

naldemedine compared to 0.2% (2/1,165) of patients taking placebo regardless of maintenance opioid 

treatment, and 0.6% (1/155) of patients with cancer and OIC taking naldemedine 200 micrograms 

compared to 0% (0/152) of patients taking placebo. Symptoms included, but were not limited to 

hyperhidrosis, chills, lacrimation increased, hot flush/flushing, pyrexia, sneezing, feeling cold, 

abdominal pain, diarrhoea, nausea, vomiting, arthralgia, myalgia, and tachycardia (see section 4.4). 

 

Gastrointestinal disorders 

Abdominal pain, diarrhoea, nausea and vomiting were the most commonly reported adverse reactions 

in clinical studies with patients with chronic non-cancer pain and OIC and with patients with cancer 

and OIC. The majority of these gastrointestinal adverse reactions were mild to moderate severity and 

resolved with treatment. The discontinuation rate due to gastrointestinal treatment emergent adverse 

events with naldemedine 200 micrograms compared to placebo was 3.2% and 1% respectively in 

patients with chronic non-cancer pain and OIC and 4.5% and 0% respectively for patients with cancer 

and OIC. 

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 



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professionals are asked to report any suspected adverse reactions via the national reporting system 

listed 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 were 

administered to healthy volunteers in clinical studies. Dose-dependent increases in 

gastrointestinal-related adverse reactions, including abdominal pain, diarrhoea, and nausea, were 

observed. 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 been 

administered to patients with OIC in clinical studies. A patient who took a single dose of naldemedine 

1 mg experienced severe drug withdrawal syndrome, including nausea and stomach cramping and was 

given esomeprazole and ondansetron for nausea and midazolam hydrochloride for stomach cramping. 

The symptoms resolved. In clinical studies, patients with OIC who were administered 0.4 mg/day 

(twice the recommended dose) over 4 weeks had an increased incidence of GI-related adverse drug 

reactions including diarrhoea and abdominal pain frequently within 1-2 days after initial dosing. 

 

Management 

There is no specific antidote for naldemedine. Naldemedine is not removed from the body by 

haemodialysis. In the event of an overdose, patients should be closely monitored for potential signs 

and symptoms of opioid withdrawal syndrome (see section 4.4) and provided with appropriate 

supportive care. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Drugs for constipation, peripheral opioid receptor antagonists, ATC code: 

A06AH05. 

 

Mechanism of action 

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. 

 

Clinical efficacy and safety 

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. 

 

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 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 non-
cancer pain and OIC. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


8 

 

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). 
 



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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. 



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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.  
 

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 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. 



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Paediatric population 

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). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

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). 

 

Distribution 

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. 

 

Biotransformation 

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.  

 

Elimination 

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 radio-

labelled naldemedine, 57.3% and 34.8% of the dose was excreted in urine and faeces for the 

[oxadiazole-
14

C]-naldemedine and 20.4% and 64.3% of the dose was excreted as the [carbonyl-
14

C]-

naldemedine in urine and faeces, respectively. Approximately 20% of the naldemedine dose is 

excreted unchanged in urine. 

 

Linearity/non-linearity 

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. 



12 

 

Pharmacokinetics in subpopulations 

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). 

 

Renal impairment 

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 end-

stage 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. 

 

Hepatic impairment 

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. 

 

5.3 Preclinical safety data 

 

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-
14

C]-naldemedine-derived radioactivity was observed in pregnant rats. 

[Carbonyl-
14

C]-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 



13 

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. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

Mannitol 

Croscarmellose sodium 

Magnesium stearate 

 

Film coating 

Hypromellose 

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 the 

original 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. 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 

 

No special requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Shionogi B.V. 

Kingsfordweg 151 

1043GR Amsterdam 

The Netherlands 

 



14 

8. MARKETING AUTHORISATION NUMBER(S) 

 

 EU/1/18/1291/001   

 EU/1/18/1291/002 

 EU/1/18/1291/003 

          EU/1/18/1291/004  
           EU/1/18/1291/005  
           EU/1/18/1291/006  
 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

  

 Date of first authorisation: 18 February 2019 

 

 

 

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. 

 

 

 

  



15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 



16 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers responsible for batch release 

Manufacturing Packaging Farmaca (MPF) bv 

Appelhof 13  

NL-8465 RX Oudehaske 

8465 RX Oudehaske 

Netherlands 

 

Manufacturing Packaging Farmaca (MPF) bv 

Neptunus 12  

NL-8448 CN Heerenveen 

8448 CN Heerenveen 

Netherlands 

 

Shionogi B.V. 

Kingsfordweg 151,  

1043GR Amsterdam 

The Netherlands 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this 

product within 6 months following authorisation.  

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the  

agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed  subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 



17 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached. 

  



18 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



19 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

  



20 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rizmoic 200 micrograms film-coated tablets 

 

naldemedine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 200 micrograms naldemedine (as tosylate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

7 film-coated tablets 

10 film-coated tablets 

28 film-coated tablets 

30 film-coated tablets 

84 film-coated tablets 

100 film-coated tablets 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from light and moisture. 



21 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Shionogi B.V. 

Kingsfordweg 151 

1043GR Amsterdam 

The Netherlands 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1291/001 7 film-coated tablets 

EU/1/18/1291/002    28 film-coated tablets 

EU/1/18/1291/003    84 film-coated tablets 

EU/1/18/1291/004         10 film-coated tablets 
EU/1/18/1291/005         30 film-coated tablets 
EU/1/18/1291/006       100 film-coated tablets 
 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Rizmoic 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

  



22 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Rizmoic 200 micrograms tablets 

 

naldemedine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Shionogi 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 

 

  



23 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



24 

Package leaflet: Information for the patient 

 

Rizmoic 200 micrograms film-coated tablets 

naldemedine 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 

- If you have any further questions, ask your doctor or pharmacist. 

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 

 

1. What Rizmoic is and what it is used for 

2. What you need to know before you take Rizmoic 

3. How to take Rizmoic 

4. Possible side effects 

5. How to store Rizmoic 

6. Contents of the pack and other information 

 

 

1. What Rizmoic is and what it is used for 

 

Rizmoic contains the active substance naldemedine. 

 

It is a medicine used in adults to treat constipation caused by pain medicines, called opioids 

(e.g morphine, oxycodone, fentanyl, tramadol, codeine, hydromorphone, methadone). 

 

Your opioid pain medicine may cause the following symptoms: 

- reduction in how often you pass stools 

- hard stools 

- stomach ache 

- pain in the rectum when pushing hard stools out 

- a feeling that the bowel is still not empty after passing stools. 

 

Rizmoic can be used in patients using an opioid medicine for cancer pain or long term non-cancer pain 

after they have previously been treated with a laxative. 

 

 

2. What you need to know before you take Rizmoic 

 

Do not take Rizmoic: 

- if you are allergic to naldemedine or any of the other ingredients of this medicine (listed in 

section 6). 

- if your bowel is blocked or perforated, or if there is a high risk of your bowel becoming 

blocked, as a blockage may cause a hole to develop in the bowel wall. 

Do not take this medicine if any of the above applies to you. If you are not sure, talk to your doctor or 

pharmacist before taking Rizmoic. 

 



25 

Warnings and precautions 

 

Talk to your doctor or pharmacist before taking Rizmoic: 

- if you suffer from a disease which may affect your bowel wall such as: 

 a stomach ulcer; 
 an enlarged colon due to a condition known as Ogilvie's syndrome; 
 diverticulitis (an illness where your gut is inflamed); 
 cancer of the bowel or peritoneum. The peritoneum is the lining of your gut area. 
 a disease causing severe inflammation of the digestive tract such as Crohn's disease . 

 

- if you have cancer of the brain or central nervous system, multiple sclerosis, or Alzheimer's 

disease. If you have these conditions and develop opioid withdrawal symptoms (see section 4) 

or if the opioid medicine no longer controls your pain, contact your doctor immediately. 

 

- if you have had a heart attack within the last 3 months or if you have other severe problems with 

your heart which cause daily symptoms 

 

- if you have severe liver disease such as alcoholic liver disease, viral liver infection or impaired 

liver function. 

 

- if you are taking certain medicines such as itraconazole to treat fungal infections, or an 

antibiotic called rifampicin to treat tuberculosis and other infections. See 'Other medicines and 

Rizmoic'. 

 

If any of the above apply to you, or you are not sure, talk to your doctor or pharmacist before taking 

Rizmoic. 

 

Talk to your doctor or pharmacist immediately whilst taking Rizmoic: 

- if you develop severe, lasting or worsening stomach pain as this could be a symptom of 

developing a hole in your bowel wall and can be life-threatening. Speak to your doctor 

immediately and stop taking Rizmoic. 

- if you suffer from symptoms of opioid withdrawal syndrome (see section 4 Possible side 

effects) which can develop within minutes to several days after taking a medicine such as 

Rizmoic. Stop taking Rizmoic and contact your doctor if you develop opioid withdrawal 

symptoms. 

- if you have severe diarrhoea or stomach ache, tell your doctor, so that the doctor can monitor 

you and treat you with rehydration and appropriate medicines if needed. 

 

Children and adolescents 

This medicine is not for children or adolescents under the age of 18 years because the effects of the 

medicine in children and adolescents are not known. 

 

Other medicines and Rizmoic 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 

Talk to your doctor or pharmacist if you are taking any of the following medicines: 

- Rifampicin, clarithromycin or telithromycin (antibiotic medicines) 

- Itraconazole or ketoconazole (medicines to treat fungal infections) 

- Ritonavir, indinavir or saquinavir (medicines for HIV infection) 

- Phenytoin, carbamazepine, phenobarbital (medicines to treat epilepsy) 

- St John’s wort (Hypericum perforatum), a herbal medicine used for depression 
 

Using these medicines with Rizmoic may affect the way naldemedine works or increase its side 

effects. 

 



26 

Rizmoic with drink 

You should not drink large amounts of grapefruit juice whilst taking Rizmoic. 

 

Pregnancy and breast-feeding 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before taking this medicine. The effects of the medicine in 

pregnant women are not known. Your doctor will advise you about whether you can use Rizmoic if 

you are pregnant. 

 

Do not breast-feed during treatment with Rizmoic as it is not known if naldemedine passes into breast 

milk. Talk to your doctor if you are already breast-feeding. 

 

Driving and using machines 

Rizmoic has no influence on your ability to drive or to use machines. 

 

Rizmoic contains sodium 

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 

‘sodium-free’. 
 

 

3. How to take Rizmoic 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

 The recommended dose is one 200 microgram tablet once daily. 
 

 You can take Rizmoic with or without laxatives. 
 

 You can take Rizmoic at any time of the day, with food or between meals. However, once you 
start taking the medicine, take it at around the same time each day. 

 

 There is no need to alter the dose of your opioid medicine before starting Rizmoic. 
 

If you stop taking your opioid medicine 

You should stop taking Rizmoic when you stop taking your opioid pain medicine. 

 

If you take more Rizmoic than you should 

If you have taken more Rizmoic than you should, talk to your doctor or go to the hospital. You will be 

monitored for opioid withdrawal symptoms (see section 2, under ‘Warnings and Precautions’, and 
section 4). 

 

If you forget to take Rizmoic 

If you miss a tablet of Rizmoic, take it as soon as you remember. 

However if it is less than 12 hours until your next dose, skip the missed dose, and wait until it is time 

to take your next tablet. 

Do not take a double dose to make up for a forgotten tablet. 

 

If you stop taking Rizmoic 

Stopping Rizmoic while continuing to take your opioid medicine may cause the constipation to return. 

Talk to your doctor if you stop taking Rizmoic. 

 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 



27 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Stop taking Rizmoic and contact your doctor if you get a combination of 3 or more of the following 

symptoms of opioid withdrawal on the same day: 

 feeling depressed 
 nausea (feeling sick) or vomiting 
 achy muscles 
 watery eyes or runny nose 
 pupils dilating 
 hairs of the skin standing on end 
 sweating 
 diarrhoea 
 yawning 
 fever 
 inability to sleep 
 

The following side effects may happen with this medicine: 

 

If you are being treated with an opioid medicine for chronic non-cancer pain. 

Rare (may affect up to 1 in 1,000 people): 

 If you experience a serious allergic reaction, stop taking Rizmoic and see a doctor or go to a 
hospital straight away.. Serious allergic reactions include: swelling of the hands, feet, ankles, 

face, lips or throat which may cause difficulty swallowing or breathing, itching of the skin and 

nettle rash.  

Common (may affect up to 1 in 10 people): 

 diarrhoea 
 stomach pain 
 nausea (feeling sick) 
 vomiting 

 

If you are being treated with an opioid medicine for cancer. 

Very common (may affect more than 1 in 10 people): 

 diarrhoea 
Common: 

 stomach pain 
 

Not Known (frequency cannot be estimated from the available data) 

 Gastrointestinal perforation (a hole developing in the bowel wall) 
 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

5. How to store Rizmoic 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the carton and blisters after EXP. The 

expiry date refers to the last day of that month. 

 

Store in the original package in order to protect the tablets from light and moisture. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


28 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Rizmoic contains 

- Each tablet contains 200 micrograms of naldemedine (as tosylate). 

- The other ingredients are: 

Tablet core: Mannitol, croscarmellose sodium (see section 2 under ‘Rizmoic contains sodium’) 
and magnesium stearate. 

 Film coating: hypromellose , talc and yellow iron oxide (E172). 

 

What Rizmoic looks like and contents of the pack 

Rizmoic is a round, approximately 6.5 mm diameter, yellow film-coated tablet debossed with '222' and 

the Shionogi logo on one side and '0.2' on the other side. 

 

The medicine is available in aluminium blisters, containing 7,10 or 14 tablets. 

Pack sizes of 7, 10, 28, 30, 84 or 100 tablets. 

Not all pack sizes may be marketed in your country. 

 

Marketing Authorisation Holder 

Shionogi B.V. 

Kingsfordweg 151 

1043GR Amsterdam 

The Netherlands 

 

Manufacturer 

Manufacturing Packaging Farmaca (MPF) B.V.,  

Neptunus 12, 

Heerenveen, 

8448CN, 

The Netherlands 

 

Manufacturing Packaging Farmaca (MPF) B.V., 

Appelhof 13, 

Oudehaske, 

8465RX, 

The Netherlands 

 

Shionogi B.V. 

Kingsfordweg 151,  

1043GR Amsterdam 

The Netherlands 

 

 

 

 

 

 

 

 

 

 

 

 



29 

 

 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

AT, BE, BG, CY, CZ, DK, EE, IE, EL, FI, FR, HR, HU, IE, 

IS, LT, LU, LV, MT, , NO, PL, PT, RO, SE, SI, SK 

Shionogi B.V. 

Tel/Tel./Teл./Tlf/Tél/Puh/Sími/Τηλ: 
+31 (0) 20 703 8327 

contact@shionogi.eu 

DE 

Hexal AG 

Tel: +49 (0)80249080 

service@hexal.com 

 

 

ES 

Shionogi SLU 

Tel: +34 911 239 258 

contacta@shionogi.eu 

 

IT 

Shionogi Srl 

Tel: +39 06 94 805 118 

 contattaci@rizmoic.it 

 

UK 

Sandoz Limited 

Tel: +44 (0) 1276 698020 

mailbox.sandoz-gb@sandoz.com 

 
PL 

Molteni Farmaceutici Polska Sp. z o.o.  

Tel.: +48 (12) 653 15 71                                                                                                                                                              

e-mail: biuro@molteni.com.pl 

 

 
NL 

Sandoz B.V. 

Tel: +31 (0)36 5241600 

info.sandoz-nl@sandoz.com 

 

 

This leaflet was last revised in 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET