MOVANTIK (naloxegol) Tablets
Company:  AstraZeneca Pharmaceuticals LP
Application No.:  204760
Approval Date: 9/16/2014

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• Approval Letter(s) (PDF)
• Printed Labeling (PDF)
• Summary Review (PDF)
• Officer/Employee List (PDF)
• Cross Discipline Team Leader Review (PDF)
• Medical Review(s) (PDF)
• Chemistry Review(s) (PDF)
• Pharmacology Review(s) (PDF)
• Statistical Review(s) (PDF)
• Microbiology Review(s) (PDF)
• Clinical Pharmacology Biopharmaceutics Review(s) (PDF)
• Risk Assessment and Risk Mitigation Review(s) (PDF)
• Proprietary Name Review(s) (PDF)
• Other Review(s) (PDF)
• Administrative Document(s) & Correspondence (PDF)

IMPORTANT SAFETY INFORMATION ABOUT MOVANTIK
•MOVANTIK™ is contraindicated in:
◦Patients with known or suspected gastrointestinal (GI) obstruction and patients at increased risk of recurrent obstruction due to the potential for GI perforation
◦Patients receiving strong CYP3A4 inhibitors (eg, clarithromycin, ketoconazole) because these medications can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms
◦Patients with a known serious or severe hypersensitivity reaction to MOVANTIK or any of its excipients
•Cases of GI perforation have been reported with the use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract. Monitor for severe, persistent, or worsening abdominal pain; discontinue if this symptom develops
•Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning, occurred in patients treated with MOVANTIK. Patients receiving methadone in the clinical trials were observed to have a higher frequency of GI adverse reactions that may have been related to opioid withdrawal than patients receiving other opioids. Patients with disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Monitor for symptoms of opioid withdrawal when using MOVANTIK in such patients
•The most common adverse reactions with MOVANTIK in clinical trials were abdominal pain (21%), diarrhea (9%), nausea (8%), flatulence (6%), vomiting (5%), headache (4%), and hyperhidrosis (3%)
INDICATION
MOVANTIK is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non‑cancer pain.
MECHANISM OF ACTION OF MOVANTIK1
Naloxegol is an antagonist of opioid binding at the mu-opioid receptor. When administered at the recommended dose levels, naloxegol functions as a peripherally acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids.
Naloxegol is a PEGylated derivative of naloxone, and is a substrate for the P-glycoprotein transporter (P-gp). Also, the presence of the PEG moiety in naloxegol reduces its passive permeability as compared with naloxone. Due to the reduced permeability and increased efflux of naloxegol across the blood-brain barrier, related to P-gp substrate properties, the CNS penetration of naloxegol is expected to be negligible at the recommended dose levels limiting the potential for interference with centrally mediated opioid analgesia.
Important Safety Information|
Prescribing Information
CLINICAL STUDIES — EFFICACY OF MOVANTIK1
The safety and efficacy of MOVANTIK were eva luated in two replicate, randomized, double-blind, placebo-controlled trials (Study 1 and Study 2†) in patients with opioid-induced constipation (OIC) and non-cancer related pain.
Patients receiving an opioid for at least four weeks before enrollment and self-reported OIC were eligible to participate. OIC was defined as <3 spontaneous bowel movements (SBMs) per week on average with at least 25% of the SBMs associated with one or more of the following conditions: (1) straining, (2) hard or lumpy stools; and (3) having a sensation of incomplete evacuation. Patients were prohibited from using laxatives other than bisacodyl rescue laxative and one-time use of an enema.
A total of 652 patients in Study 1 and 700 patients in Study 2 were randomized in a 1:1:1 ratio to receive 12.5 mg or 25 mg of MOVANTIK or placebo once daily for 12 weeks.
Primary endpoint
The primary endpoint was response defined as: ≥3 spontaneous bowel movements (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.
•An SBM was defined as a bowel movement without rescue laxative taken within the past 24 hours.
There was a statistically significant difference for the 25 mg MOVANTIK treatment group versus placebo for the primary endpoint in Study 1 and Study 2. Statistical significance for the 12.5 mg treatment group versus placebo was observed in Study 1 but not in Study 2. See Table 1 below.
 

#Response 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.
*Statistically significant: p-values based on the Cochran-Mantel-Haenszel test.
†Study 1 = KODIAC-04, Study 2 = KODIAC-05
Secondary endpoints
Response in prior laxative users with OIC symptoms
In Study 1 and Study 2, a secondary endpoint was response in a subgroup of patients (55% and 53%, respectively) who prior to enrollment, had reported using laxative(s) at least 4 out of the past 14 days with at least one of the following OIC symptoms of moderate, severe or very severe intensity: incomplete bowel movements, hard stool, straining, or sensation of needing to pass a bowel movement but unable to do so. Throughout the studies the patients were prohibited from using laxatives other than for rescue.
A statistically significantly higher percentage of patients in this subgroup responded with MOVANTIK 25mg compared to placebo (49% vs. 29% , p=0.002 in Study 1 and 47% vs. 31%, p=0.01 in Study 2) and with MOVANTIK 12.5mg compared to placebo (43% vs. 29% , p=0.03 in Study 1). This secondary endpoint was not tested for MOVANTIK 12.5 mg versus placebo in Study 2 because the primary endpoint was not statistically significant.
Time to first post-dose SBM
Another secondary endpoint was time to first post-dose SBM. The time to first post-dose SBM was significantly shorter with MOVANTIK 25 mg compared to placebo in both Study 1 (p <0.001) and Study 2 (p <0.001), and for MOVANTIK 12.5 mg as compared to placebo in Study 1 (p <0.001).
For Study 1, the median times to first post-dose SBM were 6, 20, and 36 hours with MOVANTIK 25 mg, MOVANTIK 12.5 mg, and placebo, respectively. For Study 2, the median times to first post-dose SBM were 12 and 37 hours with MOVANTIK 25 mg and placebo, respectively. These analyses do not include the results for MOVANTIK 12.5 mg versus placebo in Study 2 because the primary endpoint was not statistically significant. In the two studies, 61-70% and 58% of patients receiving MOVANTIK 25 mg and MOVANTIK 12.5 mg, respectively, had an SBM within 24 hours of the first dose.
Change in mean number of days per week with SBMs
A third secondary endpoint was an eva luation of change from baseline between the treatment groups for mean number of days per week with at least 1 SBM but no more than 3 SBM's. There was a significant difference in number of days per week with 1 to 3 SBM’s per day on average over 12 weeks between MOVANTIK 25 mg (Study 1 and Study 2) and MOVANTIK 12.5 mg (Study 1) and placebo.
CLINICAL STUDIES — ADVERSE REACTIONS1
Table 2 below lists adverse reactions in pooled Studies 1 and 2 occurring in ≥3% of patients receiving MOVANTIK

12.5 mg or 25 mg and at an incidence greater than placebo.
 

*Adverse reactions occurring in ≥ 3% of patients receiving MOVANTIK 12.5 mg or 25 mg and at an incidence greater than placebo.
New Drugs Online Report for naloxegol
Information
Generic Name: naloxegol 
Trade Name: Movantik 
Synonym: PEG-naloxol, NKTR-118 
Entry Type: New molecular entity  
Developmental Status
UK: Recommended for approval (Positive opinion) 
EU: Recommended for approval (Positive opinion) 
US: Approved (Licensed) 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Comments
Sep 14: EU positive opinion for treatment of adult patients 18 years and older with opioid-induced constipation including patients with inadequate response to laxatives [15].
29/09/2014 12:05:32
Sep 14: Approved in the US [14].
17/09/2014 11:24:14
Apr 14: A decision on approval in the US is expected 16 Sep 14 [12]
25/04/2014 14:10:40
Sep 13: EMA accepts the Marketing Authorisation Application (MAA) for naloxegol [10].
30/09/2013 10:59:57
Sep 13: Filed in the US for treatment of opioid-induced constipation in adults with chronic non-cancer pain [9].
20/09/2013 11:19:46
Aug 13: Filed in the EU [9].
20/09/2013 11:19:20
Feb 13: Plans to file for approval in the EU and US in Q3 2013 [7]
27/02/2013 08:38:18
Naloxegol is currently considered a Schedule II controlled substance by the US Drug Enforcement Administration (DEA) based on structural relatedness to noroxymorphone. AstraZeneca has conducted the studies necessary to eva luate the abuse potential and dependence-producing properties of naloxegol in support of obtaining decontrol. A petition for the decontrol of naloxegol was submitted to the DEA in March 2012 and subsequently accepted for review. [6]
13/11/2012 08:11:40
Mar 11: PIII programme started. Regulatory filings planned for 2013 [1].
18/03/2011 16:03:40
Trial or other data
Jun 14: Two RCTs (n= 652; n=700) published in NEJM found treatment with naloxegol vs. placebo resulted in significantly higher rate of treatment response at wk 12, without reducing opioid-mediated analgesia (25 mg group, response = 44.4% vs. 29.4%, p=0.001 in 1 study and 39.7% vs. 29.3%, p= 0.02 in other) [13].
09/06/2014 16:12:22
Oct 13: Results reported from the long-term safety study, KODIAC-08. Most naloxegol-emergent GI adverse events occurred early in treatment and were transient; 1.6% of patients discontinued naloxegol due to abdominal pain. Common AEs occurring more often with naloxegol than with usual care were abdominal pain (17.8% vs. 3.3%), diarrhoea (12.9% vs. 5.9%), nausea (9.4% vs. 4.1%), headache (9.0% vs. 4.8%), and flatulence (6.9% vs. 1.1%). 2 patients in each study arm had major cardiovascular AEs and these were not attributed to study drug. Two opioid withdrawal AEs were reported in patients taking naloxegol (both were deemed unrelated to naloxegol); pain scores and opioid doses were comparable between treatment groups and were stable throughout the study [11].
17/10/2013 21:32:43
Feb 13: Analysts are concerned about the implications for naloxegol of the FDA´s rejection of methlylnaltrexone in Jul 12 last summer because of concerns that people coming off therapy could be at higher risk of cardiovascular events. Both methlylnaltrexone and naloxegol are mu-opioid antagonists. Analysts have also raised the possibility that one of the PIII efficacy trials for naloxegol may have failed to meet its primary outcome as the company retrieved data from one patient after the database for the trial had been locked [8].
27/02/2013 09:37:19
Feb 13: Top level results reported from KODIAC-08, an open-label, randomised, 52-week, long-term safety trial of naloxegol 25mg once daily vs usual care (UC) in 804 patients with non-cancer related pain and opioid-induced constipation (OIC). The trial reported no imbalances in serious adverse events. There were a low number of major adverse cardiovascular events (MACE), as adjudicated by an independent external committee, and there was no imbalance of these events across naloxegol and UC arms.There were no increases from baseline levels in mean daily pain scores or mean total daily opioid dose in either the naloxegol or the UC arm [7]. 
27/02/2013 08:37:59
Nov 12: Enrolment is complete for the open-label, randomised, 52-week long-term safety trial (KODIAC-08) and the trial is expected to be completed by Q1 2013. [6]
13/11/2012 08:18:00
Nov 12: Top-line results from two PIII trials (KODIAC 04 and 05) and one safety extension trial (KODIAC 07) in patients with non-cancer-related pain and opioid-induced constipation (OIC). KODIAC 04 and 05 are 12 week RCT eva luating 12.5mg and 25mg naloxegol OD vs. placebo. Primary endpoint = % of OIC responders vs. placebo (responder defined as having at least 3 spontaneous bowel movements / week). In KODIAC 04, both doses were statistically superior to placebo (p=0.015, 12.5mg and 0.001, 25mg). In KODIAC 05, 25mg dose was statistically superior to placebo (p=0.021). The most common adverse events (AEs) in the naloxegol treatment arms in both trials were abdominal pain, diarrhoea and nausea. In KODIAC 07, the occurrence of AEs was lower than in 04 and 05, with arthralgia the most common non-serious AE reported (with 25mg). [6]
13/11/2012 08:17:17
Jun 11: NCT01384292: A 4 week PIII RCT comparing NKTR-118 (12.5 or 25mg daily) vs placebo in relieving opioid-induced constipation (OIC) in 336 patients with cancer-related pain, including those who have inadequate response to laxatives. The primary outcome measure is response, defined as having ≥3 rescue-free bowel movements (RFBMs) per week during the 4-week treatment period, with at least 1 RFBM per week increase over baseline for at least 3 out of 4 weeks. Inclusion criteria include: self-reported active symptoms of OIC at screening (<3 RFBMs/week and experiencing >1 reported symptom of hard/lumpy stools, straining, or sensation of incomplete evacuation/anorectal obstruction in at least 25% of BMs over the previous 4 weeks); documented confirmed OIC (<3 RFBMs/week on average aver the 2-week OIC confirmation period; and a total daily dose of >30 mg of oral morphine or equivalent for ≥4 weeks with no anticipated change over study period. The study started Jun 11 and is due to complete Sep 12 [5]. 
04/07/2011 11:15:17
May 11: NCT01323790 a randomized, double-blind, placebo-controlled PIII study of NKTR-118 (12.5 and 25mg) in 630 patients with non-cancer-related pain and opioid-induced constipation. The primary outcome is response (responder/non-responder) during weeks 1 to 4, where a responder is defined as having at least 3 Spontaneous Bowel Movements (SBMs)/week, with at least 1 SBM/week increase over baseline, for at least 3 out of the first 4 weeks. Study started Mar 11 and is due to complete Sep 12 [4].
06/05/2011 09:47:28
Apr 11: NCT01336205 is an open-label 52-week study to assess the long-term safety of NKTR-118 in opioid-induced constipation in 1135 patients with non-cancer-related pain. The primary outcome is the incidence, nature and intensity of adverse effects. The study will start in Apr 11 and is due to complete Dec 12 [3].
20/04/2011 09:52:29
Mar 11: NCT01309841 is randomized, double-blind, placebo-controlled study to assess the efficacy and safety of NKTR-118 (12.5mg or 25mg once daily) in patients with non-cancer-related pain and opioid-induced constipation. The primary outcome is response (responder/non-responder) during Weeks 1 to 4, where a responder is defined as having at least 3 spontaneous bowel movements (SBMs)/week, with at least 1 SBM/week increase over baseline, for at least 3 out of the first 4 weeks. Study starts Mar 11 and due to complete Aug 12 [2].
18/03/2011 16:04:46
Mar 11: The PIII programme will consist of two 12-week, randomized, placebo-controlled efficacy studies (with 630 patients each) and an open-label, randomized, long-term safety study with a ‘usual care’ comparator arm. The efficacy studies will compare response rate with two different doses of NKTR 118 vs placebo with primary endpoint at 4 weeks. There is a 3 month safety extension following one of the two 12 week studies [1]. 
18/03/2011 16:04:34
Evidence Based eva luations
NICE scope  https://www.nice.org.uk/guidance/indevelopment/gid-tag458/documents
NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/naloxegol-nktr-118-for-opioid-induced-constipation/
References  
Available only to registered users
 Category
BNF Category: Laxatives (01.06)
Pharmacology: Peripherally-acting opioid antagonist  
Epidemiology: Opioid-induced constipation is a side effect that affects nearly all patients taking opioid treatment and will persist unless treated. The preva lence of opioid-induced constipation is not known. However, in England in 2010 there were over 17 million prescriptions for opioid items. In 2010-11 there were 57,506 hospital admissions due to constipation in England, and in 2011, there were 57 deaths registered in England and Wales due to constipation.  
Indication: Opioid-induced constipation 
Additional Details:  
Method(s) of Administration  
Oral 
Company Information
Name: AstraZeneca 
US Name: AstraZeneca 
NICE Information
In timetable: Yes  
When: Jul / 2015 
Note: www.nice.org.uk/Guidance/InDevelopment/GID-TAG458 
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