RIZMOIC Film-coated tablet Ref.[27907] Active ingredients: Naldemedine

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.

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”.

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.

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).

Naldemedine has no or negligible influence on the ability to drive and use machines.

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.

Table 1. Adverse reactions presented by System Organ Class and frequency in patients with chronic non-cancer pain and opioid-induced constipation:

^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:

^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 7 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.