Moventig · 4.8 Undesirable effects · 1

HOS-216618 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile In pooled data from Clinical Studies the most commonly reported adverse reactions with naloxegol (≥ 5%) are: abdominal pain, diarrhoea, nausea, headache and flatulence. Most 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. Tabulated list of adverse reactions 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 System Organ Very Common Uncommon Rare Not known Classification Common Infections and Nasopharyngitis Infestations Immune system disorders Hypersensitivity Nervous system Headache Opioid disorders withdrawal syndrome Gastrointestinal Abdominal Flatulence, Gastrointestinal disorders paina, nausea, perforation (see diarrhoea vomiting section 4.4) 7  System Organ Very Common Uncommon Rare Not known Classification Common Skin and Hyperhidrosis subcutaneous tissue disorders 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”. Description of selected adverse reactions Opioid withdrawal syndrome Naloxegol at therapeutic doses has minimal uptake across the blood brain barrier. In some patients, however, a constellation

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HOS-216614 · has-contraindication-information · PDF-Seite 3

Hypersensitivity Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or any other opioid antagonist. Gastrointestinal obstruction Patients with known or suspected gastrointestinal (GI) obstruction or in patients at increased risk of recurrent obstruction, due to the potential for GI perforation (see section 4.4). Conditions in patients with cancer pain • Patients with underlying cancer who are at heightened risk of GI perforation, such as those with: • underlying malignancies of GI tract or peritoneum • recurrent or advanced ovarian cancer • vascular endothelial growth factor (VEGF) inhibitor treatment. 3 Strong CYP3A4 inhibitors 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.

HOS-216613 · has-indication-information · PDF-Seite 2

Moventig is indicated for the treatment of opioid-induced constipation (OIC) in adult patients who have had an inadequate response to laxative(s). For definition of inadequate response to laxative(s), see section 5.1.

HOS-216616 · has-interaction-information · PDF-Seite 5

Interaction with CYP3A4 inhibitors and inducers Interaction with strong CYP3A4 inhibitors 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). 5 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). Interaction with moderate CYP3A4 inhibitors In an open-label, non-randomized, 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. Interaction with strong CYP3A4 inducers In an open-label, non-randomized, 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). Interaction with P-gp inhibitors A double-blind, randomized, 2-pa

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HOS-216617 · has-pregnancy-information · PDF-Seite 6

Pregnancy 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). 6 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. Breast-feeding 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. Fertility 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).

HOS-216615 · has-warning-information · PDF-Seite 4

Conditions with increased potential for gastrointestinal perforation Cases of gastrointestinal (GI) 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 GI perforation. Naloxegol must not be used in patients with known or suspected GI 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 GI tract wall (e.g. severe peptic ulcer disease, Crohn’s Disease, active or recurrent diverticulitis, infiltrative GI 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. Clinically important disruptions of the blood-brain barrier 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. Concurrent methadone use Patients taking methadone as primary therapy for their pain condition were observed in Clinical Studies to have a higher frequency of GI 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.

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