Important Safety Information Full Prescribing Information
Symproic

For opioid-induced constipation 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 STUDIED IN OVER 1000 OIC PATIENTS

Two replicate, 12-week, randomized, double-blind, placebo-controlled trials

Randomization

547 patients in Study 1
and 553 patients in Study 2
randomized
in a 1:1 ratio

Symproic 0.2 mg
once daily

Placebo

12-week treatment period

Bisacodyl was used as a
rescue laxative
Study medication was administered without regard to meals

Study population

  • Eligible patients were receiving a stable opioid morphine equivalent daily dose of at least 30 mg for at least 4 weeks before enrollment and self-reported OIC
  • OIC was confirmed through a 2-week run-in period and was defined as no more than 4 spontaneous bowel movements (SBMs)* total over 14 consecutive days and fewer than 3 SBMs in a given week, with at least 25% of the SBMs associated with one or more of the following conditions:
    • Straining
    • Hard or lumpy stools
    • Sensation of incomplete evacuation
    • Sensation of anorectal obstruction/blockage
  • Patients were not using laxatives or were willing to discontinue laxatives
  • Patients were excluded if they had no BMs over the 7 consecutive days prior to and during the 2-week screening period; patients who had never taken laxatives were excluded, as well as those with evidence of significant structural abnormalities of the GI tract

*SBM was defined as a bowel movement (BM) without rescue laxative taken within the past 24 hours.

patient demographics

Mean age

54 years

Sex

59% women

Mean BMI9

31

Mean Baseline SBMs

1.3 and 1.2 per week (Studies 1 and 2, respectively)

For opioid-induced constipation 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

PROVEN EFFICACY IN TWO CLINICAL TRIALS

Endpoints are consistent with the symptoms of OIC: FREQUENCY, COMPLETENESS, and STRAINING

Primary endpoint: responder rate

To be considered a responder,
patients had to achieve:

≥3 SBMs per week Plus Change from
baseline of ≥1 SBM per week

FOR

At least 9 out of 12 weeks,
INCLUDING
3 out of the last 4 weeks

Responder rates were significantly
higher with Symproic compared
with placebo

Primary endpoint

For opioid-induced constipation 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

WITH SYMPROIC, MORE FREQUENT SBMs, MORE COMPLETE SBMs, AND MORE SBMs WITHOUT STRAINING

Statistically significant increase vs placebo in frequency of SBMs per week from baseline to week 1 and to the last 2 weeks

Secondary endpoint: Frequency

CI, confidence interval.

Change in the frequency of SBMs per week from baseline to the first week and to the last 2 weeks

The mean baseline number of SBMs was 1.3 and 1.2 per week for Studies 1 and 2, respectively.

Statistically significant increase vs placebo in frequency of complete SBMs (CSBMs) per week from baseline to the last two weeks

Secondary endpoint: Completeness

CI, confidence interval.
*Compared with placebo.

Change in frequency of CSBMs per week from baseline to the last 2 weeks

Statistically significant increase vs placebo in frequency of sbms without straining per week from baseline to the last two weeks

Secondary endpoint: Straining

CI, confidence interval.
*Compared with placebo.

Change in frequency of SBMs without straining per week from baseline to the last 2 weeks

For opioid-induced constipation 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

DEMONSTRATED TOLERABILITY WITH SYMPROIC in Studies
1, 2, and 3

Symproic has a tolerability profile established across 3 trials

Common adverse reactions occurring in ≥2% of patients

12-week data from Studies 1 and 2
Adverse
reactions*		 Symproic
n=542		 Placebo
n=546
Abdominal pain† 8% 2%
Diarrhea 7% 2%
Nausea 4% 2%
Gastroenteritis 2% 1%
Opioid Withdrawal
  • 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

* Adverse reactions occurring in at least 2% of patients receiving Symproic and at an incidence greater than placebo

† Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain.

12-week data from Study 3
Adverse
reactions*		 Symproic
n=621		 Placebo
n=619
Abdominal pain† 11% 5%
Diarrhea 7% 3%
Nausea 6% 5%
Vomiting 3% 2%
Gastroenteritis 3% 1%
Study 3: 52-week study

Randomized, double blind, placebo-controlled safety study.
Patients were allowed to maintain their current laxative therapy throughout study duration.

  • Adverse reactions up to 12 months in Study 3 are similar to those in the tables above (diarrhea 11% vs 5%,
    abdominal pain 8% vs 3%, and nausea 8% vs 6% for Symproic and placebo, respectively)
Opioid withdrawal
  • In Study 3 (52-week data), the incidence of adverse reactions of opioid withdrawal was 3% (20/621) for Symproic and 1% (9/619) for placebo

* Adverse reactions occurring in at least 2% of patients receiving Symproic and at an incidence greater than placebo

† Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper.

DOSING: WITH SYMPROIC, THERE ARE OPTIONS

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® (naldemedine). 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.

Indication

Symproic 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.

Please see Full Prescribing Information and Medication Guide for Symproic.

References: 1. Argoff CE, Brennan MJ, Camilleri M, et al. Consensus recommendations on initiating prescription therapies for opioid-induced constipation. Pain Med. 2015;16(12):2324-2337. 2. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372-380. 3. 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. 4. 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. 5. 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-e96. 6. 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. 7. Emmanuel A, Johnson M, McSkimming P, Dickerson S. Laxatives do not improve symptoms of opioid-induced constipation: results of a patient survey Pain Med. 2017;18(10):1932-1940. doi:10.1093/pm/pnw240 8. 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(10):1386-1395. 9. Hale M, Wild J, Reddy J, Yamada T, Arjona Ferreira JC. 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.