Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Kyowa Kirin Holdings B.V., Bloemlaan 2, 2132NP, Hoofddorp, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or any other opioid antagonist.
Patients with known or suspected gastrointestinal (GI) obstruction or in patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation (see section 4.4).
Patients with underlying cancer who are at heightened risk of GI perforation, such as those with:
Concomitant use with strong CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, itraconazole or telithromycin; protease inhibitors such as ritonavir, indinavir or saquinavir; grapefruit juice when consumed in large quantities), see section 4.5.
Cases of gastrointestinal perforation have been reported in the post-marketing setting, including fatal cases when naloxegol was used in patients who were at an increased risk of gastrointestinal (GI) perforation. Naloxegol must not be used in patients with known or suspected gastrointestinal obstruction or in patients at increased risk of recurrent obstruction, or in patients with underlying cancer who are at heightened risk of GI perforation (see section 4.3).
Caution with regards to the use of naloxegol should be exercised in patients with any condition which might result in impaired integrity of the gastrointestinal tract wall (e.g. severe peptic ulcer disease, Crohn’s Disease, active or recurrent diverticulitis, infiltrative gastrointestinal tract malignancies or peritoneal metastases). The overall benefit-risk profile for each patient should be taken into account. Patients should be advised to discontinue therapy with naloxegol and promptly notify their physician if they develop unusually severe or persistent abdominal pain.
Naloxegol is a peripherally acting mu-opioid receptor antagonist with restricted access to the central nervous system (CNS). The blood brain barrier integrity is important for minimizing naloxegol uptake into the CNS. Patients with clinically important disruptions to the blood-brain barrier (e.g. primary brain malignancies, CNS metastases or other inflammatory conditions, active multiple sclerosis, advanced Alzheimer’s disease etc.) were not included in clinical studies and may be at risk for naloxegol entry into the CNS. Naloxegol should be prescribed with caution in such patients taking into account their individual benefit-risk balance with observation for potential CNS effects, such as symptoms of opioid withdrawal and/or interference with opioid-mediated analgesia. If evidence for opioid-mediated interference with analgesia or opioid withdrawal syndrome occurs, patients should be instructed to discontinue Moventig and contact their physician.
Patients taking methadone as primary therapy for their pain condition were observed in clinical trials to have a higher frequency of gastrointestinal adverse reactions (such as abdominal pain and diarrhoea) than patients not receiving methadone. In a few cases, symptoms suggestive of opioid withdrawal when taking naloxegol 25 mg were observed in patients taking methadone for their pain condition. This was observed in a higher proportion of patients taking methadone than those not taking methadone. Patients taking methadone for treatment of opioid addiction were not included in the clinical development programme and use of naloxegol in these patients should be approached with caution.
Reports of severe abdominal pain and diarrhoea have been observed in clinical trials with the 25 mg dose, typically occurring shortly after initiation of treatment. There was a higher incidence of discontinuations in patients taking the 25 mg dose compared to placebo due to diarrhoea (0.7% for placebo versus 3.1% for naloxegol 25 mg) and abdominal pain (0.2% versus 2.9%, respectively). Patients should be advised to promptly report severe, persistent or worsening symptoms to their physician. Consideration may be given to lowering the dose to 12.5mg in patients experiencing severe gastrointestinal adverse events depending upon the response and tolerability of individual patients.
Cases of opioid withdrawal syndrome have been reported in the naloxegol clinical programme (DSM-5). Opioid withdrawal syndrome is a cluster of three or more of the following signs or symptoms: dysphoric mood, nausea, vomiting, muscle aches, lacrimation, rhinorrhoea, pupillary dilation, piloerection, sweating, diarrhoea, yawning, fever or insomnia. Opioid withdrawal syndrome typically develops within minutes to several days following administration of an opioid antagonist. If opioid withdrawal syndrome is suspected the patient should discontinue Moventig and contact their physician.
Naloxegol was not studied in the clinical trial programme in patients who had a recent history of myocardial infarction within 6 months, symptomatic congestive heart failure, overt cardiovascular (CV) disease or patients with a QT interval of ≥ 500 msec. Moventig should be used with caution in these patients. A QTc study performed with naloxegol in healthy volunteers did not indicate any prolongation of the QT interval.
Naloxegol is not recommended in patients who are taking strong CYP3A4 inducers (e.g. carbamazepine, rifampin, St. John’s Wort) (see section 4.5).
For information regarding concomitant use with CYP3A4 inhibitors, see sections 4.2, 4.3 and 4.5.
The starting dose for patients with moderate or severe renal insufficiency is 12.5 mg. If side effects impacting tolerability occur, naloxegol should be discontinued. The dose can be increased to 25 mg if 12.5 mg is well tolerated by the patient (see section 5.2).
Naloxegol has not been studied in patients with severe hepatic impairment. The use of naloxegol is not recommended in such patients.
There is limited clinical experience with the use of naloxegol in OIC patients with cancer-related pain. Therefore, caution should be used when prescribing naloxegol to such patients (see section 4.3).
This medicinal product contains less than 1 mmol sodium (23 mg) per 12.5 mg/25 mg tablet, that is to say essentially ‘sodium-free’.
In an open-label, non-randomized, fixed-sequence, 3-period, 3-treatment, crossover study to evaluate the effect of multiple doses of ketoconazole on the single dose PK of naloxegol, co-administration of ketoconazole and naloxegol resulted in a 12.9 fold (90% CI: 11.3-14.6) increase in naloxegol AUC and a 9.6-fold increase in naloxegol Cmax (90% CI: 8.1-11.3), compared to when naloxegol was administered alone. Therefore, concomitant use with strong CYP3A4 inhibitors is contraindicated (see section 4.3). Grapefruit juice has been classified as a potent CYP3A4 inhibitor when consumed in large quantities. No data are available on the concomitant use of naloxegol with grapefruit juice. Concomitant consumption of grapefruit juice while taking naloxegol should generally be avoided and considered only in consultation with a healthcare provider (see section 4.3).
In an open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, crossover study to evaluate the effect of multiple doses of diltiazem on the single dose PK of naloxegol, co-administration of diltiazem and naloxegol resulted in a 3.4-fold (90% CI: 3.2-3.7) increase in naloxegol AUC and a 2.9-fold increase in naloxegol Cmax (90% CI: 2.6-3.1), compared to when naloxegol was administered alone. Therefore, a dose adjustment of naloxegol is recommended when co-administered with diltiazem and other moderate CYP3A4 inhibitors (see section 4.2). The starting dose for patients taking moderate CYP3A4 inhibitors is 12.5 mg once daily and the dose can be increased to 25 mg if 12.5 mg is well tolerated by the patient (see section 4.2).
No dosage adjustment is required for patients taking weak CYP3A4 inhibitors.
In an open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, single-dose, crossover study to evaluate the effect of multiple doses of rifampin on the single dose PK of naloxegol, co-administration of rifampin and naloxegol resulted in a 89% (90% CI: 88%-90%) decrease in naloxegol AUC and a 76% decrease in naloxegol Cmax (90% CI: 69%-80%), compared to when naloxegol was administered alone. Therefore, Moventig is not recommended in patients who are taking strong CYP3A4 inducers (see section 4.4).
A double-blind, randomized, 2-part, crossover, single centre study was conducted to evaluate the effect of quinidine on the pharmacokinetics of naloxegol and the effect of the co-administration of naloxegol and quinidine on morphine-induced miosis in healthy volunteers. Co-administration of the P-gp inhibitor quinidine resulted in a 1.4 fold increase in the AUC (90% CI: 1.3-1.5) and a 2.4 fold increase in the Cmax (90% CI: 2.2-2.8) of naloxegol. Co-administration of naloxegol and quinidine did not antagonize the morphine-induced miosis effect, suggesting that P-gp inhibition does not meaningfully change the capacity of naloxegol to cross the blood-brain barrier at therapeutic doses.
As the effects of P-gp inhibitors on the PK of naloxegol were small relative to the effects CYP3A4 inhibitors, the dosing recommendations for Moventig when co-administered with medicinal products causing both P-gp and CYP3A4 inhibition should be based on CYP3A4 inhibitor status – strong, moderate or weak (see sections 4.2, 4.3 and 4.5).
Use of naloxegol with another opioid antagonist (e.g. naltrexone, naloxone) should be avoided due to the potential for an additive effect of opioid receptor antagonism and an increased risk of opioid withdrawal.
Interaction studies have only been performed in adults.
There are limited data from the use of naloxegol in pregnant women.
Studies in animals have shown reproductive toxicity where systemic exposures were several times above the therapeutic exposure level (see section 5.3).
There is a theoretical potential for provoking opioid withdrawal in the foetus with use of an opioid receptor antagonist in the mother, who is being treated with a concurrent opioid. Naloxegol use is therefore not recommended during pregnancy.
It is unknown whether naloxegol is excreted in human milk. Available toxicological data in rats have shown naloxegol excreted 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 naloxegol could provoke opioid withdrawal in a breast-fed neonate whose mother is taking an opioid receptor agonist. Therefore, use in breast-feeding mothers is not recommended.
The effect of naloxegol on fertility in humans has not been studied. Naloxegol was found to have no effect on fertility of male and female rats at oral doses up to 1,000 mg/kg per day (greater than 1,000 times the human therapeutic exposure (AUC) at the recommended human dose of 25 mg/day).
Moventig has no or negligible influence on the ability to drive and use machines.
In the pooled data from clinical trials the most commonly reported adverse reactions with naloxegol (≥5%) are: abdominal pain, diarrhoea, nausea, headache and flatulence. The majority of gastrointestinal adverse reactions were graded as mild to moderate, occurred early in treatment and resolved with continued treatment. They were often reported as having a component of cramping discomfort.
Adverse reactions are classified according to frequency and System Organ Class. Frequency categories are defined according to the following conventions: 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 (cannot be estimated from the available data).
Table 1. Adverse reactions by System Organ Class (SOC) and frequency:
Common: Nasopharyngitis
Not known: Hypersensitivity
Common: Headache
Uncommon: Opioid withdrawal syndrome
Very Common: Abdominal paina, diarrhoea
Common: Flatulence, nausea, vomiting
Not known: Gastrointestinal perforation (see section 4.4)
Common: Hyperhidrosis
Note: Selection of ADRs and their frequencies based on the 25 mg dose.
a Reflects MedDRA Preferred Terms of: “abdominal pain”, “abdominal pain upper”, “abdominal pain lower” and “gastrointestinal pain”.
Naloxegol at therapeutic doses has minimal uptake across the blood brain barrier. In some patients, however, a constellation of symptoms has been reported, which resembles the syndrome of central opioid withdrawal. Most such reports were observed shortly after initial administration with the medicinal product and were mild or moderate in intensity.
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 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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