Market Overview

Fifty-Two Week Safety Study on Symproic® (naldemedine) for Opioid-induced Constipation (OIC) in Adults with Chronic Non-cancer Pain Published in PAIN

Share:

First 52-Week Randomized, Double-blind, Placebo-controlled Study to
Evaluate the Safety of a Peripherally-acting Mu-opioid Receptor
Antagonist (PAMORA)

Shionogi
Inc.
 and Purdue
Pharma L.P.
today announced the publication of a study known as
COMPOSE-3. The study is the first to investigate a peripherally-acting
mu-opioid receptor antagonist (PAMORA) over the course of 52 weeks in a
randomized, placebo-controlled and double-blind manner. The study was published
online ahead of print in PAIN, the journal of the International
Association for the Study of Pain.

"The publication of the results of COMPOSE-3 in PAIN is
significant as the study provides additional important information
regarding the safety and tolerability of Symproic over the course of 52
weeks for adults with OIC and chronic non-cancer pain," said Dr. Tsutae
"Den" Nagata, Chief Medical Officer, Shionogi.

Study Design and Results
This randomized, double-blind,
placebo-controlled, parallel-group, Phase 3 clinical trial (COMPOSE-3)
evaluated the long-term safety and tolerability of once-daily oral
Symproic 0.2 mg for 52 weeks in patients with chronic non-cancer pain,
on a stable opioid therapy, and who could be on a routine laxative
regimen but still had OIC.

In the study, 2,414 patients were screened. Patients had to be aged 18
to 80, have had chronic non-cancer pain for at least 3 months, were
receiving a stable daily dose of opioids (greater than or equal to 30 mg
oral morphine equivalents) for at least one month prior to screening,
and had self-reported OIC. From the patients screened, 1,246 eligible
patients with confirmed OIC were randomized 1:1 to receive once-daily
oral Symproic 0.2 mg (n=623) or placebo (n=623) for 52 weeks.

The primary endpoint was summary measures of treatment-emergent adverse
events (TEAEs). Similar proportions of patients taking Symproic and
placebo experienced TEAEs (Symproic, 68.4% (n=425) vs placebo 72.1%
(n=446); difference: −3.6% [95% CI: −8.7-1.5]) and TEAEs leading to
study discontinuation (Symproic 6.3% vs placebo 5.8%; difference: 0.5%
[95% CI: –2.2-3.1]). Diarrhea was the most common TEAE in the Symproic
group (11%) and was reported more frequently vs placebo (5.3%;
difference: 5.6% [95% CI: 2.6-8.6]). A greater proportion of patients
treated with Symproic vs placebo reported other gastrointestinal-related
treatment-emergent adverse events, including abdominal pain (8.2% vs
3.1%) and vomiting (6.0% vs 3.1%). The incidences of treatment-related
serious adverse events (Symproic, 0.5% vs placebo, 1.0%; difference:
−0.5% [95% CI: −1.4-0.5]) and serious TEAEs leading to study
discontinuation (Symproic, 1.1% vs placebo, 1.9%; difference: −0.8% [95%
CI: −2.2-0.6]) were consistent between treatment groups.

The 52-week safety study included efficacy endpoints as well, which were
secondary. One of these endpoints, frequency of bowel movements, was
also assessed in the primary endpoint of the two 12-week pivotal
studies, and the results were consistent.

"We are pleased to share with the scientific community the publication
of the first 52-week double-blind study evaluating the safety of a
PAMORA in adult patients with OIC and chronic non-cancer pain," said
Monica Kwarcinski, PharmD, Head of Medical Affairs, Purdue Pharma L.P.
"In collaboration with our partners at Shionogi, we are committed to
supporting adult patients who live with OIC and chronic non-cancer pain
and the physicians who treat them."

Symproic, a once-daily oral PAMORA medication approved by the U.S. Food
and Drug Administration (FDA) in March 2017, is indicated for the
treatment of OIC in adult patients with chronic non-cancer pain,
including patients with chronic pain related to prior cancer or its
treatment who do not require frequent (e.g., weekly) opioid dosage
escalation. Symproic is available as a 0.2 mg once-daily oral tablet and
may be taken at any time of day, with or without food, and with or
without laxatives. Alteration of analgesic dosing regimen prior to
initiating Symproic is not required. Patients receiving opioids for less
than 4 weeks may be less responsive to Symproic. Treatment with Symproic
should be discontinued if treatment with the opioid medicine is also
discontinued.

Please see Important Safety Information, including Warnings &
Precautions and Adverse Reactions below
.

About Opioid-Induced Constipation
Constipation is one of the
most commonly reported side effects associated with opioid treatment,
including among patients with chronic non-cancer pain.1,2 When
opioids bind to specific proteins called mu-opioid receptors in the
gastrointestinal (GI) tract, constipation may occur. Opioid-induced
constipation (OIC) is a result of increased fluid absorption and reduced
GI motility due to opioid receptor binding in the GI tract. OIC is
defined as a change in bowel habits that is characterized by any of the
following after initiating opioid therapy: reduced bowel movement
frequency, development or worsening of straining to pass bowel
movements, a sense of incomplete rectal evacuation, or harder stool
consistency.3 In patients with chronic non-cancer pain, the
prevalence of OIC ranges from approximately 40-50 percent.4-7

INDICATION
Symproic® (naldemedine) is
indicated for the treatment of opioid-induced constipation (OIC) in
adult patients with chronic non-cancer pain, including patients with
chronic pain related to prior cancer or its treatment who do not require
frequent (e.g., weekly) opioid dosage escalation.

Important Safety Information about Symproic

CONTRAINDICATIONS

  • Patients with known or suspected gastrointestinal (GI) obstruction and
    patients at increased risk of recurrent obstruction, due to the
    potential for GI perforation.
  • Patients with a history of a hypersensitivity reaction to Symproic.
    Reactions have included bronchospasm and rash.

WARNINGS AND PRECAUTIONS
Cases of GI perforation have been
reported with 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 the development of severe, persistent, or worsening
abdominal pain; discontinue if this symptom develops.

Symptoms consistent with opioid withdrawal, including hyperhidrosis,
chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing,
feeling cold, abdominal pain, diarrhea, nausea, and vomiting have
occurred in patients treated with Symproic.

Patients having disruptions to the blood-brain barrier may be at
increased risk for opioid withdrawal or reduced analgesia. Take into
account the overall risk-benefit profile when using Symproic in such
patients. Monitor for symptoms of opioid withdrawal in such patients.

DRUG INTERACTIONS

Avoid use with strong CYP3A inducers (e.g., rifampin) because they may
reduce the efficacy of Symproic.

Use with moderate (e.g., fluconazole) and strong (e.g., itraconazole)
CYP3A inhibitors and P-glycoprotein inhibitors (e.g., cyclosporine) may
increase Symproic concentrations. Monitor for potential adverse
reactions.

Avoid use of Symproic with another opioid antagonist due to potential
for additive effect and increased risk of opioid withdrawal.

USE IN SPECIFIC POPULATIONS
Symproic crosses the placenta
and may precipitate opioid withdrawal in a fetus due to the immature
fetal blood-brain barrier. Symproic should be used during pregnancy only
if the potential benefit justifies the potential risk. Because of the
potential for serious adverse reactions, including opioid withdrawal in
breastfed infants, a decision should be made to discontinue
breastfeeding or discontinue the drug, taking into account the
importance of the drug to the mother.

Avoid use in patients with severe hepatic impairment. No dose adjustment
of Symproic is required in patients with mild or moderate hepatic
impairment.

ADVERSE REACTIONS
The most common adverse reactions with
Symproic as compared to placebo in clinical trials were: abdominal pain
(8% vs 2%), diarrhea (7% vs 2%), nausea (4% vs 2%), and gastroenteritis
(2% vs 1%).

In pooled Studies 1 and 2, the incidence of adverse reactions of opioid
withdrawal was 1% (8/542) for Symproic and 1% (3/546) for placebo. In
Study 3 (52-week data), the incidence was 3% (20/621) for Symproic and
1% (9/619) for placebo.

To report suspected Adverse Reactions, contact Shionogi at
1-800-849-9707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Full Prescribing Information including Medication Guide
for Symproic at 
www.symproic.com/pi.

About Shionogi
Shionogi & Co., Ltd., is a Japanese
pharmaceutical company with a 139-year history discovering and
developing innovative therapies. Shionogi Inc., the U.S. based
subsidiary of Shionogi & Co., Ltd., continues this focus on the
development and commercialization of high quality medicines that protect
the health and well-being of the patients we serve. The company
currently markets products in several therapeutic areas including
anti-infectives, pain and cardiovascular diseases. Our pipeline is
focused on infectious disease, pain, CNS and oncology. For more details
on Shionogi Inc., visit www.shionogi.com.
For more information on Shionogi & Co., Ltd., visit www.shionogi.co.jp/en.

About Purdue Pharma L.P.
Purdue Pharma L.P. is a privately
held pharmaceutical company headquartered in Stamford, Conn. Purdue
Pharma is part of a network of independent associated companies
dedicated to providing patients and providers with innovative medicines.
The company's leadership and employees are committed to serving
healthcare professionals, patients and caregivers by providing quality
products and educational resources that make a positive impact on
healthcare — and on lives. For more information, please visit www.purduepharma.com.

REFERENCES

1 Coyne KS, LoCasale RJ, Datto CJ, Sexton CC, Yeomans K, Tack
J. Opioid-induced constipation in patients with chronic noncancer pain
in the USA, Canada, Germany, and the UK: descriptive analysis of
baseline patient-reported outcomes and retrospective chart review. Clinicoecon
Outcomes Res.
2014;6: 269-281.
2 Moore RA, McQuay
HJ. Prevalence of opioid adverse events in chronic non-malignant pain:
systematic review of randomised trials of oral opioids. Arthritis Res
Ther.
2005;7:R1046-R1051.
3 Camilleri M, Drossman
DA, Becker G, Webster LR, Davies AN, Mawe GM. Emerging treatments in
neurogastroenterology: a multidisciplinary working group consensus
statement on opioid-induced constipation. Neurogastroenterol
Motil
. 2014; 26:1386-1395.
4 Kalso E, Edwards JE,
Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic
review of efficacy and safety. Pain. 2004;112:372–380.
5 Cook
SF, Lanza L, Zhou X, et al. Gastrointestinal side effects in chronic
opioid users: results from a population-based survey. Aliment
Pharmacol Ther
. 2008;27(12):1224-1232.
6 Brown RT,
Zuelsdorff M, Fleming M. Adverse effects and cognitive function among
primary care patients taking opioids for chronic nonmalignant pain. J
Opioid Manag
. 2006;2(3):137–146.
7 Tuteja AK,
Biskupiak J, Stoddard GJ, Lipman AG. Opioid-induced bowel disorders and
narcotic bowel syndrome in patients with chronic non-cancer pain. Neurogastroenterol
Motil
. 2010;22(4):424-430.

View Comments and Join the Discussion!