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Shionogi Inc. and Purdue Pharma L.P. Announce U.S. Availability of Symproic® (naldemedine) for the Treatment of Opioid-Induced Constipation in Adults with Chronic Non-Cancer Pain

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Shionogi
Inc.
 and Purdue
Pharma L.P.
announced today that Symproic® (naldemedine)
0.2 mg tablets are now available throughout the United States. The U.S.
Food and Drug Administration (FDA) approved Symproic as a once-daily
oral tablet 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.

Symproic was descheduled, or removed from the controlled substance
classification list, by the U.S. Drug Enforcement Administration (DEA)
on September 29, 2017.

"We are very pleased to launch Symproic with our partner, Purdue Pharma,
in the U.S. Together we are providing a new treatment option for many
adult patients with chronic non-cancer pain who suffer from
opioid-induced constipation. We are committed to addressing this
important need for the management of chronic non-cancer pain patients,"
said John Keller, president and chief executive officer, Shionogi Inc.

Symproic is a peripherally-acting mu-opioid receptor antagonist
(PAMORA). Symproic comes 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.

"At Purdue Pharma, we are committed to delivering innovative products
that improve the health of patients. The launch of Symproic marks an
important milestone, as we continue to diversify our portfolio to
provide more comprehensive care for patients," said Craig Landau, MD,
chief executive officer, Purdue Pharma L.P. "We are delighted to partner
with Shionogi to bring Symproic to patients across the U.S. who are
suffering from OIC, a potentially severe condition that affects many
individuals who are on opioid medication to manage chronic non-cancer
pain. Symproic is a new oral treatment option that helps to address the
underlying mechanism of OIC, by blocking opioids from binding to
mu-opioid receptors in tissues such as those in the gastrointestinal
tract, thereby decreasing the constipating effects of opioids."

The FDA approval of Symproic was based on data from the global Phase 3
COMPOSE clinical trial program, which enrolled 2346 patients with OIC
and chronic non-cancer pain. It was comprised of three studies: COMPOSE
1, COMPOSE 2 and COMPOSE 3. COMPOSE 1 and 2 were two replicate, 12-week,
randomized, double-blind, placebo-controlled trials, while COMPOSE 3 was
a 52-week, randomized, double-blind, placebo-controlled, long-term
safety study.

For the primary endpoint, the proportion of responders was significantly
higher with Symproic versus placebo in COMPOSE 1 (48%; n = 273 versus
35%; n = 272, p=0.0020) and COMPOSE 2 (53%; n = 276 versus 34%; n = 274,
p<0.0001). A responder was defined as a patient who had at least 3
spontaneous bowel movements (SBMs) per week and a change from baseline
of at least 1 SBM per week for at least 9 out of the 12 weeks including
3 out of the last 4 weeks.1

Treatment with Symproic resulted in a statistically significant increase
versus placebo in frequency from baseline in all secondary endpoints
including frequency of SBMs per week to week 1 and to the last 2 weeks
of the treatment period and in the frequency of complete SBMs and SBMs
without straining per week to the last 2 weeks of the treatment period.1
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%).

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.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 from baseline 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 taking
opioids, 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

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 accompanying Full Prescribing Information including
Medication Guide for Symproic or visit 
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 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 Hale M, et al. Naldemedine
versus placebo for opioid-induced constipation (COMPOSE-1 and
COMPOSE-2): two multicentre, phase 3, double-blind, randomised,
parallel-group trials
. Lancet Gastroenterol Hepatol.
2017;2(8)555-564.
2 Sehgal N, Colson J, Smith HS.
Chronic pain treatment with opioid analgesics: benefits versus harms of
long-term therapy. Expert Rev Neurother. 2013;13:1201-1220.
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;112:372-80.
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.

MR-03930

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