MOVENTIG 25mg film-coated tablets medication leaflet

Moventig 12.5 mg film-coated tablets

Moventig 25 mg film-coated tablets

Moventig 12.5 mg film-coated tablets

Each film-coated tablet contains naloxegol oxalate equivalent to 12.5 mg naloxegol.

Moventig 25 mg film-coated tablets

Each film-coated tablet contains naloxegol oxalate equivalent to 25 mg naloxegol.

For the full list of excipients, see section 6.1.

Moventig 12.5 mg film-coated tablet (tablet).

Oval, 10.5x5.5 mm, mauve tablet.

Moventig 25 mg film-coated tablet (tablet).

Oval, 13x7 mm, mauve tablet.

Tablets are engraved with “nGL” on one side and the strength of the tablet on the other.

Moventig is indicated for the treatment of opioid-induced constipation (OIC) in adult patients whohave had an inadequate response to laxative(s).

For definition of inadequate response to laxative(s), see section 5.1.

The recommended dose of Moventig is 25 mg once daily.

Moventig may be used with or without laxatives. Moventig treatment must be withdrawn whensystemic opioid therapy is stopped.

No dose adjustment is recommended based on age (see section 5.2).

The starting dose for patients with moderate or severe renal insufficiency is 12.5 mg. If side effectsimpacting tolerability occur, naloxegol should be discontinued. The dose can be increased to 25 mg if12.5 mg is well tolerated by the patient (see section 5.2).

No dosage adjustment is required for patients with mild renal impairment.

No dose adjustment is required for patients with mild to moderate hepatic impairment.

Safety and efficacy have not been established in patients with severe hepatic impairment (seesection 5.2). Use in patients with severe hepatic impairment is not recommended.

The starting dose for patients taking moderate CYP3A4 inhibitors (e.g. diltiazem, verapamil) is12.5 mg once daily. The dose can be increased to 25 mg if 12.5 mg is well tolerated by the patient (seesection 4.5).

No dose adjustment is required for patients taking weak CYP3A4 inhibitors (e.g. alprazolam,atorvastatin (see section 4.5).

Patients with cancer related pain

No dose adjustment is required for patients with cancer related pain (see section 4.3).

The safety and efficacy of naloxegol in children <18 years of age has not yet been established.

No data are available.

Oral use.

It is recommended that Moventig is taken in the morning, for patient convenience to avoid bowelmovements in the middle of the night.

Moventig should be taken on an empty stomach at least 30 minutes prior to the first meal of the day or2 hours after the first meal of the day.

For patients who are unable to swallow the tablet whole, the tablet can be crushed to a powder andmixed in half a glass of water (120 ml) and drunk immediately. The glass should be rinsed with afurther half glass of water (120 ml) and the contents drunk. Refer to section 6.6 for further informationon administration through a nasogastric tube.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or any otheropioid antagonist.

Gastrointestinal obstruction

Patients with known or suspected gastrointestinal (GI) obstruction or in patients at increased risk ofrecurrent 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.

Strong CYP3A4 inhibitors

Concomitant use with strong CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, itraconazole ortelithromycin; protease inhibitors such as ritonavir, indinavir or saquinavir; grapefruit juice whenconsumed in large quantities), see section 4.5.

Conditions with increased potential for gastrointestinal perforation

Cases of gastrointestinal (GI) perforation have been reported in the post-marketing setting, includingfatal 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 atincreased risk of recurrent obstruction, or in patients with underlying cancer who are at heightened riskof GI perforation (see section 4.3).

Caution with regards to the use of naloxegol should be exercised in patients with any condition whichmight 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 beadvised to discontinue therapy with naloxegol and promptly notify their physician if they developunusually 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 centralnervous system (CNS). The blood brain barrier integrity is important for minimizing naloxegol uptakeinto the CNS.

Patients with clinically important disruptions to the blood-brain barrier (e.g. primary brainmalignancies, 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 entryinto the CNS. Naloxegol should be prescribed with caution in such patients taking into account theirindividual benefit-risk balance with observation for potential CNS effects, such as symptoms of opioidwithdrawal 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 wereobserved in patients taking methadone for their pain condition. This was observed in a higherproportion of patients taking methadone than those not taking methadone.

Patients taking methadone for treatment of opioid addiction were not included in the clinicaldevelopment 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 Studies with a 25 mgdose, typically occurring shortly after initiation of treatment.

There was a higher incidence of discontinuations in patients taking a 25 mg dose compared to placebodue 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 orworsening symptoms to their physician.

Consideration may be given to lowering the dose to 12.5mg in patients experiencing severe GI adverseevents depending upon the response and tolerability of individual patients.

Opioid withdrawal syndrome

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 typicallydevelops within minutes to several days following administration of an opioid antagonist.

If opioid withdrawal syndrome is suspected the patient should discontinue Moventig and contact theirphysician.

Patients with Cardiovascular conditions

In interventional Clinical Studies of naloxegol, patients who had a recent history of myocardialinfarction within 6 months, symptomatic congestive heart failure, overt cardiovascular disease orpatients with a QT interval of ≥ 500 msec were not studied (see section 5.1). Moventig should be usedwith caution in these patients.

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

QT interval (see section 5.1).

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, pct. 4.3 and 4.5.

The starting dose for patients with moderate or severe renal insufficiency is 12.5 mg. If side effectsimpacting tolerability occur, naloxegol should be discontinued. The dose can be increased to 25 mg if12.5 mg is well tolerated by the patient (see sections 4.2 and 5.2).

Naloxegol has not been studied in patients with severe hepatic impairment. The use of naloxegol is notrecommended in such patients.

Moventig contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 12.5 mg/25 mg tablet, that isto say essentially ‘sodium-free’.

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 evaluatethe effect of multiple doses of ketoconazole on the single dose PK of naloxegol, co-administration ofketoconazole and naloxegol resulted in a 12.9 fold (90% CI: 11.3-14.6) increase in naloxegol AUCand a 9.6-fold increase in naloxegol Cmax (90% CI: 8.1-11.3), compared to when naloxegol wasadministered alone. Therefore, concomitant use with strong CYP3A4 inhibitors is contraindicated (seesection 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. Concomitantconsumption of grapefruit juice while taking naloxegol should generally be avoided and consideredonly 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 evaluatethe effect of multiple doses of diltiazem on the single dose PK of naloxegol, co-administration ofdiltiazem 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 administeredalone.

Therefore, a dose adjustment of naloxegol is recommended when co-administered with diltiazem andother 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 welltolerated 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 studyto 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 wasadministered 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-part, crossover, single centre study was conducted to evaluate theeffect of quinidine on the pharmacokinetics of naloxegol and the effect of the co-administration ofnaloxegol 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 foldincrease in the Cmax (90% CI: 2.2-2.8) of naloxegol. Co-administration of naloxegol and quinidine didnot antagonize the morphine-induced miosis effect, suggesting that P-gp inhibition does notmeaningfully 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 CYP3A4inhibitors, the dosing recommendations for Moventig when co-administered with medicinal productscausing both P-gp and CYP3A4 inhibition should be based on CYP3A4 inhibitor status - strong,moderate or weak (see sections 4.2, pct. 4.3 and 4.5).

Interaction with other opioid antagonists

Use of naloxegol with another opioid antagonist (e.g. naltrexone, naloxone) should be avoided due tothe potential for an additive effect of opioid receptor antagonism and an increased risk of opioidwithdrawal.

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 timesabove the therapeutic exposure level (see section 5.3).

There is a theoretical potential for provoking opioid withdrawal in the foetus with use of an opioidreceptor antagonist in the mother, who is being treated with a concurrent opioid. Naloxegol use istherefore not recommended during pregnancy.

It is unknown whether naloxegol is excreted in human milk. Available toxicological data in rats haveshown naloxegol excreted 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 naloxegol could provoke opioidwithdrawal in a breast-fed neonate whose mother is taking an opioid receptor agonist. Therefore, usein breast-feeding mothers is not recommended.

The effect of naloxegol on fertility in humans has not been studied. Naloxegol was found to have noeffect on fertility of male and female rats at oral doses up to 1,000 mg/kg per day (greater than1,000 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 pooled data from Clinical Studies the most commonly reported adverse reactions with naloxegol(≥ 5%) are: abdominal pain, diarrhoea, nausea, headache and flatulence. Most gastrointestinal adversereactions were graded as mild to moderate, occurred early in treatment and resolved with continuedtreatment. They were often reported as having a component of cramping discomfort.

Adverse reactions are classified according to frequency and System Organ Class. Frequencycategories 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

Classification Common Common Uncommon Rare Not known

Infections and Nasopharyngitis

Infestations

Immune systemdisorders Hypersensitivity

Nervous system Headache Opioiddisorders withdrawalsyndrome

Gastrointestinal Abdominal Flatulence, Gastrointestinaldisorders paina, nausea, perforation (seediarrhoea vomiting section 4.4)

System Organ Very

Classification Common Common Uncommon Rare Not known

Skin and Hyperhidrosissubcutaneous tissuedisorders

Note: Selection of ADRs and their frequencies based on the 25 mg dosea Reflects MedDRA Preferred Terms of: “abdominal pain”, “abdominal pain upper”, “abdominal pain lower” and“gastrointestinal pain”.

Opioid withdrawal syndrome

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 centralopioid withdrawal. Most such reports were observed shortly after initial administration with themedicinal product and were mild or moderate in intensity.

Reporting 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.

Doses of naloxegol up to 1,000 mg were administered in healthy volunteers in Clinical Studies. Apotential CNS effect (reversal of opioid-induced miosis, as measured by pupillometry) was observedin 1 volunteer in the 250 mg group and 1 volunteer in the 1,000 mg group. In a Clinical Study ofpatients with OIC, a daily dose of 50 mg was associated with an increased incidence of intolerablegastrointestinal effects (primarily abdominal pain).

No antidote is known for naloxegol and dialysis was noted to be ineffective as a means of eliminationin a Clinical Study in patients with renal failure.

If a patient on opioid therapy receives an overdose of naloxegol, the patient should be monitoredclosely for potential evidence of opioid withdrawal symptoms or reversal of central analgesic effect. Incases of known or suspected overdose of naloxegol, symptomatic treatment as well as monitoring ofvital functions should be performed.

The use of naloxegol in the paediatric population has not been studied.

Pharmacotherapeutic group: Drugs for constipation, peripheral opioid receptor antagonists

ATC code: A06AH03

Mechanism of action and pharmacodynamic effects

Naloxegol is a PEGylated derivative of the mu-opioid receptor antagonist naloxone. PEGylationreduces naloxegol’s passive permeability and also renders the compound a substrate for the

P-glycoprotein transporter. Due to poorer permeability and increased efflux of naloxegol across theblood-brain barrier, related to P-gp substrate properties, the CNS penetration of naloxegol is minimal.

In vitro studies demonstrate that naloxegol is a full neutral antagonist at the mu-opioid receptor.

Naloxegol acts by binding to mu-opioid receptors in the gastrointestinal (GI) tract targeting theunderlying causes of OIC (i.e. reduced GI motility, hypertonicity and increased fluid absorptionresulting from long-term opioid treatment).

Naloxegol functions as a peripherally-acting mu-opioid receptor antagonist in the GI tract, therebydecreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects onthe central nervous system.

In a thorough QT/QTc study, as defined by ICH E14 Guideline, there were no clinically importantchanges in HR, RR, QT, PR or QRS intervals or T wave morphology observed. In addition, no safetyand tolerability concerns were identified in this study up to the highest dose given (150 mg).

According to ICH E14 Guideline, this is considered a definitively negative thorough QT/QTc study.

OIC in patients with non-cancer related pain

The efficacy and safety of naloxegol in patients with OIC and non-cancer related pain wereestablished in two replicate double-blind, placebo-controlled Clinical Studies (Kodiac 4 and

Kodiac 5). Patients taking oral opioids at a minimum dose of 30 morphine milligram equivalent (mme)per day for at least 4 weeks before enrolment and self-reported OIC were eligible.

OIC was confirmed through a two week run in period and defined as < 3 spontaneous bowelmovements (SBMs) per week on average with constipation symptoms associated with at least 25% ofbowel movements. Patients were prohibited from using laxatives other than bisacodyl rescue laxativeif they had not had a bowel movement for 72 hours. SBM was defined as a bowel movement withoutrescue laxative taken within the past 24 hours.

Patients with mean Numeric Rating Scale (NRS) pain scores equal to or higher than 7 were not studieddue to the risk of confounding the efficacy as a result of uncontrolled pain. Patients who had a QTcF>500 msec at screening, had a recent history of myocardial infarction within 6 months beforerandomization, had symptomatic congestive heart failure, or had any other overt CV disease wereexcluded from the Clinical Studies.

Patients with moderate or severe hepatic insufficiency (Child’s-Pugh Class B or C) were excludedfrom the Phase III Clinical Studies (Kodiac 4 and 5). Therefore, naloxegol has not been studied in OICpatients with moderate or severe hepatic impairment.

Both Clinical Studies were powered and stratified so that at least 50% of patients randomized to eachtreatment arm met baseline criteria to be categorized as a laxative inadequate responder (LIR).

Definition of laxative inadequate responder

To qualify as LIR, in the two weeks prior to first study visit patients had to have reported concurrent

OIC symptoms of at least moderate severity whilst taking at least one laxative class for a minimum offour days during the pre-study period.

Response over 12 weeks in the LIR group

Efficacy and durability of effect were measured in the primary end-point as response over a 12-weektreatment period to naloxegol as defined by > 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 first ofthree multiplicity protected secondary endpoints was the 12-week responder rate in the LIR subgroup.

There was a statistically significant difference for the 25 mg dose versus placebo for the LIR subgroupresponder rate in Kodiac 4 (p=0.002) and Kodiac 5 (p=0.014). Under multiplicity testing procedure,statistical significance for the 12.5 mg treatment group versus placebo in the LIR subgroup wasobserved in Kodiac 4 (p=0.028) but not in Kodiac 5 (p=0.074). In Kodiac 4, response rates in theplacebo, 12.5 mg and 25 mg groups in the LIR subgroup were 28.8%, 42.6% and 48.7%, while in

Kodiac 5, the corresponding response rates were 31.4, 42.4% and 46.8%. In pooled data from

Kodiac 4 and Kodiac 5, responder rates in the LIR subgroup were 30.1% for placebo, 42.5% for the12.5 mg dose, and 47.7% for the 25 mg dose, with the relative risk (95% CI) for treatment effectversus placebo of 1.410(1.106, 1.797) and 1.584(1.253, 2.001) for the 12.5 mg and 25 mg groups,respectively.

Response over 12 weeks in patients with an inadequate response to at least two classes of laxative

Response to naloxegol over 12 weeks was tested in a sub-group of patients with inadequate responseto at least two laxative classes, corresponding to approximately 20% of patients randomized. In apooled analysis of Kodiac 4 and Kodiac 5 (90, 88 and 99 patients in the placebo, 12.5 mg and 25 mggroups respectively), higher response rates in this population were observed for the 25 mg dose groupcompared with placebo (p=0.040). The responder rates in this population were placebo 30.0%,12.5 mg 44.3% and 25 mg 44.4%.

Time to first spontaneous bowel movement

The time to first SBM in the LIR subgroup after taking the first dose was shorter for the 25 mg dose ascompared to placebo in Kodiac 4 (p<0.001) and Kodiac 5 (p=0.002). The 12.5 mg dose in the LIRsubgroup also demonstrated shorter time to first post-dose SBM as compared to placebo in Kodiac 4(p=0.002) and Kodiac 5 (p<0.001). In Kodiac 4, placebo, 12.5 mg and 25 mg dose had median time tofirst post dose SBM of 43.4, 20.6, and 5.4 hours, respectively. In Kodiac 5 the corresponding times tofirst post dose SBM were 38.2, 12.8, and 18.1 hours, respectively.

Mean number of days per week with at least one SBM

There was an increase in the mean number of days per week with at least one SBM in the LIRsubgroup for the 25 mg dose in Kodiak 4 and Kodiac 5 (p<0.001 in both studies) and for the 12.5 mgdose (p=0.006 in both studies).

OIC symptom improvement

The 25 mg dose in the LIR subgroup improved rectal straining (Kodiac 4 p=0.043, Kodiac 5 p<0.001).

Stool consistency in the LIR subgroup as measured by the Bristol stool scale improved in Kodiac 5versus placebo (p<0.001) but not in Kodiac 4 (p=0.156). The 25 mg dose in the LIR subgroupincreased mean days per week compared with placebo with at least 1 complete spontaneous bowelmovement (CSBM) in both studies (Kodiac 4 p=0.002, Kodiac 5 p<0.001).

Symptom responder end-point

A “symptom responder” was defined as meeting both the 12-week responder criteria anddemonstrating improvement in pre-specified OIC symptoms and no deterioration in symptoms. In the

LIR subgroup, the 25 mg dose increased the symptom responder rates in both studies as compared toplacebo (Kodiac 4 p=0.001, Kodiac 5 p=0.005). The LIR subgroup symptom responder rates in

Kodiac 4 for placebo, 12.5 mg and 25 mg arms were 24.6%, 36.5% and 45.3% and the symptomresponder rates in Kodiac 5 were 25.6%, 33.6% and 42.7%.

Patient assessment of constipation symptoms (PAC-SYM) questionnaire

Naloxegol 25 mg dose in the LIR subgroup resulted in a greater improvement (change from baseline)of patient assessment of constipation symptoms (PAC-SYM) total scores compared with placebo inboth studies at 12 weeks (Kodiac 4 p=0.023, Kodiac 5 p=0.002). The 12.5 mg dose in the LIRsubgroup also resulted in greater improvement in total PAC SYM at week 12 compared with placeboin both studies (p= 0.020 and p=0.001 respectively). Naloxegol 25 mg dose, compared with placebo,also resulted in greater improvement (change from baseline) of week 12 PAC-SYM rectal domainscores in both studies (p=0.004 and p<0.001, Kodiac 4 and 5, respectively) and for the stool domainscores in Kodiac 4 (p=0.031) and Kodiac 5 (p<0.001). There was no relevant impact on abdominalsymptoms in either study (p=0.256 and p=0.916, Kodiac 4 and 5, respectively).

Potential for interference with opioid-mediated analgesia

There were no clinically relevant differences between naloxegol 12.5 mg, 25 mg, and placebo inaverage pain intensity, daily opioid dose or in opioid withdrawal scores over the 12-week study.

In the 12-week Clinical Studies (Kodiac 4 and 5), the frequency of back pain AEs was 4.3% fornaloxegol 25 mg versus 2.0% for placebo, and the frequency of extremity pain AEs was 2.2% fornaloxegol 25 mg, versus 0.7% for placebo. In a long-term safety study (Kodiac 8), the frequency of

AE reports of back pain was 8.9% for naloxegol 25 mg versus 8.8% for usual care. For extremitypain, the rate for naloxegol 25 mg was 3.5% versus 3.3% for usual care.

Safety and tolerability over an extended 12-week period

Kodiac 7 was a 12-week safety extension that allowed for patients from Kodiac 4 to continue the sameblinded treatment for an additional 12 weeks (placebo, naloxegol 12.5 mg or 25 mg daily). Theprimary objective was to compare safety and tolerability among the three treatment groups for anadditional 12 weeks (beyond that observed in Kodiac 4) using descriptive statistics. In this study,naloxegol at doses of 12.5 mg and 25 mg was generally safe and well tolerated as compared withplacebo in the treatment of OIC patients with non-cancer related pain.

In all treatment groups, including placebo, improvements in PAC-SYM domains observed in Kodiac 4were maintained for patients continuing in Kodiac 7.

Long-term safety and tolerability

Kodiac 8 was a Phase III, 52-week, multi-center, open-label, randomized, parallel group, safety andtolerability study of naloxegol versus usual care in the treatment of OIC in patients with non-cancerrelated pain. The primary objective was to assess long-term safety and tolerability for naloxegol 25 mgand to compare with usual care treatment using descriptive statistics.

Eligible patients were randomized in a 2:1 ratio to receive either naloxegol 25 mg daily (qd) or usualcare treatment for OIC for 52 weeks. Patients assigned to usual care followed a laxative treatmentregimen for OIC determined by the investigator according to best clinical judgment, excludingperipheral mu-opioid receptor antagonists.

Of the 844 patients who were randomized, 61.1% completed the study (defined as completing the2-week follow-up visit after the 52-week treatment period). Overall, 393 and 317 patients had at least6 and 12 months exposure to naloxegol 25 mg, respectively, in this study, which met the specifiedexposure requirements.

Long-term exposure to naloxegol 25 mg, up to 52 weeks, was generally safe and well tolerated in thetreatment of OIC patients with non-cancer related pain. During the 52-week treatment period therewere no important unexpected differences in the safety and tolerability findings between the naloxegol25 mg treatment group and the usual care treatment group.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Moventig in one or more subsets of the paediatric population in opioid induced constipation (seesection 4.2 for information on paediatric use).

Following oral administration, naloxegol is absorbed rapidly, with peak concentrations (Cmax) achievedat less than 2 hours. In most subjects, a secondary plasma concentration peak of naloxegol wasobserved approximately 0.4 to 3 hours after the first peak. Enterohepatic recirculation may be anexplanation as extensive biliary excretion was seen in the rat.

Food effects: A high-fat meal increased the extent and rate of naloxegol absorption. The Cmax and areaunder the plasma concentration-time curve (AUC) were increased by approximately 30% and 45%,respectively.

Naloxegol as a crushed tablet mixed in water, given orally, or administered through a nasogastric (NG)tube into the stomach, is bioequivalent to the whole tablet, with a median tmax of 0.75 and 1.50 hours(range 0.23 to 5.02 hours) for the crushed tablet given orally and the crushed tablet given via NG tube,respectively.

The mean apparent volume of distribution during the terminal phase (Vz/F) in healthy volunteersranged from 968 to 2,140 L across dosing groups and studies. Results from a QWBA (Quantitative

Whole Body Autoradiography) study in the rat and the lack of antagonism of CNS opiate effects inhumans at naloxegol doses less than 250 mg, indicate minimal distribution of naloxegol into the CNS.

Plasma protein binding of naloxegol in humans was low and the fraction unbound ranged from 80% to100%.

In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine and faeces.

These metabolites represented more than 32% of the administered dose and were formed via

N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain. None of the metaboliteswere present in > 10% of the plasma concentrations of parent or total parent and metabolite relatedmaterial.

Following oral administration of radiolabelled naloxegol, 68% and 16% of total administered dosewere recovered in the faeces and urine, respectively. Parent naloxegol excreted in the urine accountedfor less than 6% of the total administered dose. Thus, renal excretion is a minor clearance pathway fornaloxegol.

In clinical pharmacology studies, the half-life of naloxegol at therapeutic dose ranged from 6-11 hours.

Across the range of doses evaluated peak plasma concentration and AUC increased in a dose-proportional, or approximately dose proportional, manner.

Age and gender

There is a small effect of age on the pharmacokinetics of naloxegol (approximately 0.7% increase in

AUC for every year increase in age). No dose adjustment is recommended for elderly patients.

Patients over 65 years of age have been represented in the phase III Clincal Studies.

Clinical Studies of naloxegol did not include sufficient numbers of patients aged 75 years or over todetermine whether they respond differently than younger patients, however, based on the mode ofaction of the active substance there are no theoretical reasons for any requirement for dose adjustmentsin this age group.

For dose recommendations for patients with moderate or severe renal insufficiency, see section 4.2.

There is no gender effect on the PK of naloxegol.

The effect of race on the pharmacokinetics of naloxegol is small (approximately 20% decrease in the

AUC of naloxegol when other groups are compared to Caucasian) and, therefore, no dose adjustmentis necessary.

Naloxegol exposure was found to increase with increased weight, however, the differences inexposure were not considered clinically relevant.

As renal clearance is a minor route of elimination for naloxegol, regardless of severity (i.e. moderate,severe and end stage renal failure), the impact of renal impairment on the pharmacokinetics ofnaloxegol was minimal in most subjects. However, in 2 out of 8 patients (in both the moderate andsevere renal impairment groups but not in the end stage renal failure group) up to 10-fold increases inthe exposure of naloxegol were observed. In these patients renal impairment may adversely affectother clearance pathways (hepatic/gut drug metabolism, etc.) resulting in higher exposure.

The starting dose for patients with moderate or severe renal insufficiency is 12.5 mg. If side effectsimpacting tolerability occur, naloxegol should be discontinued. The dose can be increased to 25 mg if12.5 mg is well tolerated by the patient (see section 4.2).

Exposure of naloxegol in end-stage renal disease (ESRD) patients on haemodialysis was similar tohealthy volunteers with normal renal function.

Less than 20% decrease in AUC and 10% decrease in Cmax were observed in patients with mild andmoderate hepatic impairment (Child-Pugh Class A and B).

Effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol wasnot evaluated. Use in patients with severe hepatic impairment is not recommended.

The pharmacokinetics of naloxegol in the paediatric population has not been studied.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and fertility.

Embryo-foetal development studies were conducted in rats and rabbits. A potentially treatment-relatedincreased incidence of the skeletal variant bipartite vertebral centrum and a single foetus withanorchism was seen at the highest dose tested in the rat embryo-foetal development study. A possibletreatment-related foetal skeletal malformation of fused arches was noted at highest dose tested in therabbit embryo-foetal development study, in the absence of maternal toxicity. In a separate pre- andpost-natal development study in rats, body weights were lower for male pups following maternaladministration at the high dose. All these effects were observed only at exposures consideredsufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Carcinogenicity studies of naloxegol were conducted in rats and mice. In male rats, a dose-relatedincrease in Leydig cell adenomas and interstitial cell hyperplasia was observed at exposuresconsidered sufficiently in excess of the maximum human exposure. The observed neoplastic changesare well known hormonal and centrally mediated effects in the rat which are not relevant for humans.

Studies in suckling rats have shown that naloxegol is excreted in the milk.

Tablet coremannitol (E421)cellulose microcrystalline (E460)croscarmellose sodium (E468)magnesium stearate (E470b)propyl gallate (E310)

Tablet coathypromellose (E464)titanium dioxide (E171)macrogol (E1521)iron oxide red (E172)iron oxide black (E172)

Not applicable.

4 years.

Store below 25°C.

Alu/alu blister.

12.5 mg film-coated tablets

Pack sizes of 30 and 90 film-coated tablets in non-perforated blisters.

Pack sizes of 30 x 1 and 90 x 1 film-coated tablets in perforated unit dose blisters.

25 mg film-coated tablets

Pack sizes of 10, 30 and 90 film-coated tablets in non-perforated blisters.

Pack sizes of 10 x 1, 30 x 1, 90 x 1 and 100 x 1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

No special requirements for disposal. Any unused medicinal product or waste material should bedisposed of in accordance with local requirements.

The mixture can also be administered via a nasogastric (NG) tube (CH8 or greater), in this case thetablet can be crushed to a powder and mixed with water (120 ml). It is important to flush the NG tubethrough with water after administration of the mixture.

Grünenthal GmbH

Zieglerstraße 652078 Aachen

Germany

EU/1/14/962/001

EU/1/14/962/002

EU/1/14/962/003

EU/1/14/962/004

EU/1/14/962/005

EU/1/14/962/006

EU/1/14/962/007

EU/1/14/962/008

EU/1/14/962/009

EU/1/14/962/010

EU/1/14/962/011

Date of first authorisation: 8 December 2014

Date of latest renewal: 23 September 2019

Detailed information on this medicinal product is available on the website of the European Medicines

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