These Highlights Do Not Include All The Information Needed To Use Symproic Safely And Effectively. See Full Prescribing Information For Symproic.

Opioid Withdrawal

In Studies 1, 2 and 3, adverse reactions consistent with opioid withdrawal were based on investigator assessment and adjudicated based upon the occurrence of at least 3 adverse reactions potentially related to opioid withdrawal with onset of a constellation of those symptoms occurring on the same day or within one day of each other.

Adverse reactions of possible opioid withdrawal could include non-gastrointestinal (GI) symptoms (e.g., hyperhidrosis, hot flush or flushing, chills, tremor, tachycardia, anxiety, agitation, yawning, rhinorrhea, increased lacrimation, sneezing, feeling cold, and pyrexia), GI symptoms (e.g., vomiting, diarrhea, or abdominal pain), or both GI and non-GI symptoms.

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. Most SYMPROIC treated subjects experienced nearly equal incidence of GI only or both GI and non-GI symptoms.

Store SYMPROIC in a light resistant container at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Single doses of naldemedine up to 100 mg (500 times the recommended dose) and multiple doses of up to 30 mg (150 times the recommended dose) for 10 days have been administered to healthy subjects in clinical studies. Dose-dependent increases in gastrointestinal-related adverse reactions, including abdominal pain, diarrhea, and nausea, were observed.

Single doses of naldemedine up to 3 mg (15 times the recommended dose) and multiple doses of 0.4 mg (twice the recommended dose) for 28 days have been administered to patients with OIC in clinical studies. Dose-dependent increases in gastrointestinal-related adverse reactions, including abdominal pain, diarrhea, nausea, and vomiting, were observed. Also, chills, hyperhidrosis, and dizziness were reported more frequently at 1 and 3 mg doses and hyperhidrosis at the 0.4 mg dose.

No antidote for naldemedine is known. Hemodialysis is not an effective means to remove naldemedine from the blood [see Clinical Pharmacology (12.3)].

SYMPROIC (naldemedine), an opioid antagonist, contains naldemedine tosylate as the active ingredient.

The chemical name for naldemedine tosylate is: 17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3,6,14-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]morphinan-7-carboxamide 4-methylbenzenesulfonic acid.

The structural formula is:

The empirical formula for naldemedine tosylate is C₃₂H₃₄N₄O₆∙C₇H₈O₃S and the molecular weight is 742.84.

Naldemedine tosylate is a white to light tan powder, soluble in dimethylsulfoxide and methanol, slightly soluble in alcohol and water, and independent of pH.

SYMPROIC (naldemedine) tablets for oral use contain 0.2 mg naldemedine (equivalent to 0.26 mg of naldemedine tosylate).

Excipients are: D-mannitol, croscarmellose sodium, magnesium stearate, hypromellose, talc, and yellow ferric oxide.

The recommended dosage of SYMPROIC is 0.2 mg orally once daily with or without food.

The safety and effectiveness of SYMPROIC have not been established in pediatric patients.

Of the 1163 patients exposed to SYMPROIC in clinical studies, 183 (16%) were 65 years of age and over, while 37 (3%) were 75 years and over. No overall differences in safety or effectiveness between these and younger patients were observed, but greater sensitivity of some older individuals cannot be ruled out. In a population pharmacokinetic analysis, no age-related alterations in the pharmacokinetics of naldemedine were observed [see Clinical Pharmacology (12.3)].

• 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 [see Clinical Studies (14)].
• Discontinue SYMPROIC if treatment with the opioid pain medication is also discontinued.

SYMPROIC was evaluated in two replicate, 12-week, randomized, double-blind, placebo-controlled trials (Study 1 and Study 2) in which SYMPROIC was used without laxatives in patients with OIC and chronic non-cancer pain.

Patients receiving a stable opioid morphine equivalent daily dose of at least 30 mg for at least 4 weeks before enrollment and self-reported OIC were eligible for clinical trial participation.

Patients with evidence of significant structural abnormalities of the GI tract were not enrolled in these trials.

In Studies 1 and 2, patients had to either be not using laxatives or willing to discontinue laxative use at the time of screening and willing to use only the provided rescue laxatives during the screening and treatment periods.

In Studies 1 and 2, OIC was confirmed through a two-week run in period and was defined as no more than 4 spontaneous bowel movements (SBMs) total over 14 consecutive days and less than 3 SBMs in a given week with at least 25% of the SBMs associated with one or more of the following conditions: (1) straining; (2) hard or lumpy stools; (3) having a sensation of incomplete evacuation; and (4) having a sensation of anorectal obstruction/blockage.

An SBM was defined as a bowel movement (BM) without rescue laxative taken within the past 24 hours. Patients with no BMs over the 7 consecutive days prior to and during the 2-week screening period or patients who had never taken laxatives were excluded.

In the screening and treatment periods, bisacodyl was used as rescue laxative if patients had not had a BM for 72 hours and were allowed one-time use of an enema, if after 24 hours of taking bisacodyl they still had not had a BM.

A total of 547 patients in Study 1 and 553 patients in Study 2 were randomized in a 1:1 ratio to receive SYMPROIC 0.2 mg once daily or placebo for 12 weeks. Study medication was administered without regard to meals.

The mean age of subjects in Studies 1 and 2 was 54 years; 59% were women; and 80% were white. The most common types of pain in Studies 1 and 2 were back or neck pain (61%). The mean baseline number of SBMs was 1.3 and 1.2 per week for Studies 1 and 2, respectively.

Prior to enrollment, patients were using their current opioid for a mean duration of approximately 5 years. A wide range of types of opioids were used. The mean baseline opioid morphine equivalent daily dosage was 132 mg and 121 mg per day for Studies 1 and 2, respectively.

The efficacy of SYMPROIC was assessed in Studies 1 and 2 using a responder analysis. A responder was defined as a patient who had at least 3 SBMs per week and a change from baseline of at least 1 SBM per week for at least 9 out of the 12 weeks and 3 out of the last 4 weeks in Studies 1 and 2.

The responder rates in Studies 1 and 2 are shown in Table 4.

In Studies 1 and 2, the mean increase in frequency of SBMs per week from baseline to the last 2 weeks of the 12-week treatment period was 3.1 for SYMPROIC vs. 2.0 for placebo (difference 1.0, 95% CI 0.6, 1.5), and 3.3 for SYMPROIC vs. 2.1 for placebo (difference 1.2, 95% CI 0.8, 1.7), respectively.

During week 1 of the treatment period, the mean increase in frequency of SBMs per week from baseline was 3.3 for SYMPROIC vs. 1.3 for placebo (difference 2.0, 95% CI 1.5, 2.5) in Study 1 and 3.7 for SYMPROIC vs. 1.6 for placebo (difference 2.1, 95% CI 1.5, 2.6) in Study 2.

The mean increase in the frequency of complete SBM (CSBM) per week from baseline to the last 2 weeks of 12-week treatment period was 2.3 for SYMPROIC vs. 1.5 for placebo (difference 0.8, 95% CI 0.4, 1.2) in Study 1 and 2.6 for SYMPROIC vs. 1.6 for placebo (difference 1.1, 95% CI 0.6, 1.5) in Study 2. A CSBM was defined as a SBM that was associated with a sense of complete evacuation.

The change in the frequency of SBMs without straining per week from baseline to the last 2 weeks of the treatment period was 1.3 for SYMPROIC vs. 0.7 for placebo (difference 0.6, 95% CI 0.2, 0.9) in Study 1 and 1.8 for SYMPROIC vs. 1.1 for placebo (difference 0.7, 95% CI 0.3, 1.2) in Study 2.

SYMPROIC is contraindicated in:

• Patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation [see Warnings and Precautions (5.1)].
• Patients with a history of a hypersensitivity reaction to naldemedine. Reactions have included bronchospasm and rash [see Adverse Reactions (6.1)].

Serious and important adverse reactions described elsewhere in labeling include:

• Gastrointestinal perforation [see Warnings and Precautions (5.1)]
• Opioid withdrawal [see Warnings and Precautions (5.2)]

Table 3 includes drugs with clinically important drug interactions with SYMPROIC and instructions for preventing or managing the interaction.

Use of opioids induces slowing of gastrointestinal motility and transit. Antagonism of gastrointestinal mu-opioid receptors by naldemedine inhibits opioid-induced delay of gastrointestinal transit time.

Clusters of 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 [see Adverse Reactions (6.1)].

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.

The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naldemedine has not been evaluated. Avoid use of SYMPROIC in patients with severe hepatic impairment. No dose adjustment of SYMPROIC is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)].

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.

Naldemedine is an opioid antagonist with binding affinities for mu-, delta-, and kappa-opioid receptors. Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids.

Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB). Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Based on these properties, the CNS penetration of naldemedine is expected to be negligible at the recommended dose levels, limiting the potential for interference with centrally-mediated opioid analgesia.

• Gastrointestinal perforation: Consider the overall risk benefit in patients with known or suspected lesions of the GI tract. Monitor for severe, persistent, or worsening abdominal pain; discontinue if development of symptoms (5.1)
• Opioid withdrawal: Consider the overall risk benefit in patients with disruptions to the blood-brain barrier. Monitor symptoms of opioid withdrawal (5.2)

Administration ( 2.1 ):

• 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
• Discontinue SYMPROIC if treatment with the opioid pain medication is also discontinued

Dosage ( 2.2 ):

• In adults, the recommended dosage is 0.2 mg once daily with or without food

Tablets: 0.2 mg naldemedine; supplied as yellow, round, film-coated, debossed with Shionogi marking above the identifier code 222 on one side and 0.2 on the other side.

The following adverse reactions have been identified during post-approval use of SYMPROIC. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders: Gastrointestinal perforation [see Warnings and Precautions (5.1) ].

• Pregnancy: May precipitate opioid withdrawal in a fetus (8.1)
• Lactation: Discontinue drug or breastfeeding taking into consideration importance of drug to mother (8.2)
• Hepatic Impairment: Avoid in severe impairment (8.6)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to SYMPROIC in 1163 patients in clinical trials, including 487 patients with exposures greater than six months and 203 patients with exposures of 12 months.

The following safety data are derived from three double-blind, placebo-controlled trials in patients with OIC and chronic non-cancer pain: two 12-week studies (Studies 1 and 2) and one 52-week study (Study 3) [see Clinical Studies (14)].

In Studies 1 and 2, patients on laxatives were required to discontinue their use prior to study enrollment. All patients were restricted to bisacodyl rescue treatment during the study. In Study 3, approximately 60% of patients in both treatment groups were on a laxative regimen at baseline; patients were allowed to continue using their laxative regimen throughout the study duration. The safety profile of SYMPROIC relative to placebo was similar regardless of laxative use.

Tables 1 and 2 list common adverse reactions occurring in at least 2% of patients receiving SYMPROIC and at an incidence greater than placebo. Table 1 shows pooled 12-week data from Studies 1 and 2. Table 2 shows 12-week data from Study 3.

Adverse reactions up to 12 months in Study 3 are similar to those listed in Tables 1 and 2 (diarrhea: 11% vs. 5%, abdominal pain: 8% vs. 3%, and nausea: 8% vs. 6% for SYMPROIC and placebo, respectively).

Cases of gastrointestinal (GI) perforation have been reported with use of another peripherally acting opioid antagonist, including SYMPROIC. Postmarketing cases of GI perforation, including fatal cases, were reported when SYMPROIC was used in patients at risk of GI perforation (e.g., GI cancer, past GI surgery, diverticulitis, chemotherapy/radiation). SYMPROIC is contraindicated in patients with known or suspected gastrointestinal obstruction or in patients at risk of recurrent obstruction. Take into account the overall risk-benefit profile when using SYMPROIC in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue SYMPROIC in patients who develop this symptom.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

SYMPROIC is supplied as 0.2 mg naldemedine tablets as follows:

• bottle of 30 tablets - NDC 59385-041-30

7 Tablets

Each tablet contains 0.2 mg of naldemedine

(equivalent to 0.26 mg of naldemedine tosylate).

Usual adult dosage: See package insert.

Store at 20°C to 25°C (68°F to 77°F).

Mfd. for BioDelivery Sciences International, Inc.

Raleigh, NC 27612

Symproic^®

(naldemedine) tablets

0.2 mg

NDC 59385-041-07   Rx ONLY

Keep out of reach of children.

PHYSICIAN SAMPLES NOT FOR SALE

319623 04/19 SYM-0001.1b

DAY 1

DAY 2

DAY 3

DAY 4

DAY 5

DAY 6

DAY 7

LOT:

EXP:

NDC 59385-041-07

7 Tablets

Dosage: Take 1 tablet

once daily

Each tablet contains 0.2 mg of

naldemedine (equivalent to

0.26 mg of naldemedine tosylate).

Please see the included

Prescribing Information.

Keep out of reach of children.

Dispense the enclosed Medication Guide

to each patient.

Symproic^®

(naldemedine) tablets

0.2 mg

PHYSICIAN SAMPLES NOT FOR SALE

FOR ORAL USE ONLY

Rx ONLY

NDC 59385-041-30

Rx ONLY

30 Tablets

Symproic^®

(naldemedine) tablets

0.2 mg

Dispense the enclosed Medication Guide

to each patient.

Collegium_®

PHARMACEUTICAL

© 2023 Collegium Pharmaceutical, Inc.

Stoughton, MA 02072

Opioid Withdrawal

In Studies 1, 2 and 3, adverse reactions consistent with opioid withdrawal were based on investigator assessment and adjudicated based upon the occurrence of at least 3 adverse reactions potentially related to opioid withdrawal with onset of a constellation of those symptoms occurring on the same day or within one day of each other.

Adverse reactions of possible opioid withdrawal could include non-gastrointestinal (GI) symptoms (e.g., hyperhidrosis, hot flush or flushing, chills, tremor, tachycardia, anxiety, agitation, yawning, rhinorrhea, increased lacrimation, sneezing, feeling cold, and pyrexia), GI symptoms (e.g., vomiting, diarrhea, or abdominal pain), or both GI and non-GI symptoms.

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. Most SYMPROIC treated subjects experienced nearly equal incidence of GI only or both GI and non-GI symptoms.

Store SYMPROIC in a light resistant container at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Single doses of naldemedine up to 100 mg (500 times the recommended dose) and multiple doses of up to 30 mg (150 times the recommended dose) for 10 days have been administered to healthy subjects in clinical studies. Dose-dependent increases in gastrointestinal-related adverse reactions, including abdominal pain, diarrhea, and nausea, were observed.

Single doses of naldemedine up to 3 mg (15 times the recommended dose) and multiple doses of 0.4 mg (twice the recommended dose) for 28 days have been administered to patients with OIC in clinical studies. Dose-dependent increases in gastrointestinal-related adverse reactions, including abdominal pain, diarrhea, nausea, and vomiting, were observed. Also, chills, hyperhidrosis, and dizziness were reported more frequently at 1 and 3 mg doses and hyperhidrosis at the 0.4 mg dose.

No antidote for naldemedine is known. Hemodialysis is not an effective means to remove naldemedine from the blood [see Clinical Pharmacology (12.3)].

SYMPROIC (naldemedine), an opioid antagonist, contains naldemedine tosylate as the active ingredient.

The chemical name for naldemedine tosylate is: 17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3,6,14-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]morphinan-7-carboxamide 4-methylbenzenesulfonic acid.

The structural formula is:

The empirical formula for naldemedine tosylate is C₃₂H₃₄N₄O₆∙C₇H₈O₃S and the molecular weight is 742.84.

Naldemedine tosylate is a white to light tan powder, soluble in dimethylsulfoxide and methanol, slightly soluble in alcohol and water, and independent of pH.

SYMPROIC (naldemedine) tablets for oral use contain 0.2 mg naldemedine (equivalent to 0.26 mg of naldemedine tosylate).

Excipients are: D-mannitol, croscarmellose sodium, magnesium stearate, hypromellose, talc, and yellow ferric oxide.

The recommended dosage of SYMPROIC is 0.2 mg orally once daily with or without food.

The safety and effectiveness of SYMPROIC have not been established in pediatric patients.

Of the 1163 patients exposed to SYMPROIC in clinical studies, 183 (16%) were 65 years of age and over, while 37 (3%) were 75 years and over. No overall differences in safety or effectiveness between these and younger patients were observed, but greater sensitivity of some older individuals cannot be ruled out. In a population pharmacokinetic analysis, no age-related alterations in the pharmacokinetics of naldemedine were observed [see Clinical Pharmacology (12.3)].

• 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 [see Clinical Studies (14)].
• Discontinue SYMPROIC if treatment with the opioid pain medication is also discontinued.

SYMPROIC was evaluated in two replicate, 12-week, randomized, double-blind, placebo-controlled trials (Study 1 and Study 2) in which SYMPROIC was used without laxatives in patients with OIC and chronic non-cancer pain.

Patients receiving a stable opioid morphine equivalent daily dose of at least 30 mg for at least 4 weeks before enrollment and self-reported OIC were eligible for clinical trial participation.

Patients with evidence of significant structural abnormalities of the GI tract were not enrolled in these trials.

In Studies 1 and 2, patients had to either be not using laxatives or willing to discontinue laxative use at the time of screening and willing to use only the provided rescue laxatives during the screening and treatment periods.

In Studies 1 and 2, OIC was confirmed through a two-week run in period and was defined as no more than 4 spontaneous bowel movements (SBMs) total over 14 consecutive days and less than 3 SBMs in a given week with at least 25% of the SBMs associated with one or more of the following conditions: (1) straining; (2) hard or lumpy stools; (3) having a sensation of incomplete evacuation; and (4) having a sensation of anorectal obstruction/blockage.

An SBM was defined as a bowel movement (BM) without rescue laxative taken within the past 24 hours. Patients with no BMs over the 7 consecutive days prior to and during the 2-week screening period or patients who had never taken laxatives were excluded.

In the screening and treatment periods, bisacodyl was used as rescue laxative if patients had not had a BM for 72 hours and were allowed one-time use of an enema, if after 24 hours of taking bisacodyl they still had not had a BM.

A total of 547 patients in Study 1 and 553 patients in Study 2 were randomized in a 1:1 ratio to receive SYMPROIC 0.2 mg once daily or placebo for 12 weeks. Study medication was administered without regard to meals.

The mean age of subjects in Studies 1 and 2 was 54 years; 59% were women; and 80% were white. The most common types of pain in Studies 1 and 2 were back or neck pain (61%). The mean baseline number of SBMs was 1.3 and 1.2 per week for Studies 1 and 2, respectively.

Prior to enrollment, patients were using their current opioid for a mean duration of approximately 5 years. A wide range of types of opioids were used. The mean baseline opioid morphine equivalent daily dosage was 132 mg and 121 mg per day for Studies 1 and 2, respectively.

The efficacy of SYMPROIC was assessed in Studies 1 and 2 using a responder analysis. A responder was defined as a patient who had at least 3 SBMs per week and a change from baseline of at least 1 SBM per week for at least 9 out of the 12 weeks and 3 out of the last 4 weeks in Studies 1 and 2.

The responder rates in Studies 1 and 2 are shown in Table 4.

In Studies 1 and 2, the mean increase in frequency of SBMs per week from baseline to the last 2 weeks of the 12-week treatment period was 3.1 for SYMPROIC vs. 2.0 for placebo (difference 1.0, 95% CI 0.6, 1.5), and 3.3 for SYMPROIC vs. 2.1 for placebo (difference 1.2, 95% CI 0.8, 1.7), respectively.

During week 1 of the treatment period, the mean increase in frequency of SBMs per week from baseline was 3.3 for SYMPROIC vs. 1.3 for placebo (difference 2.0, 95% CI 1.5, 2.5) in Study 1 and 3.7 for SYMPROIC vs. 1.6 for placebo (difference 2.1, 95% CI 1.5, 2.6) in Study 2.

The mean increase in the frequency of complete SBM (CSBM) per week from baseline to the last 2 weeks of 12-week treatment period was 2.3 for SYMPROIC vs. 1.5 for placebo (difference 0.8, 95% CI 0.4, 1.2) in Study 1 and 2.6 for SYMPROIC vs. 1.6 for placebo (difference 1.1, 95% CI 0.6, 1.5) in Study 2. A CSBM was defined as a SBM that was associated with a sense of complete evacuation.

The change in the frequency of SBMs without straining per week from baseline to the last 2 weeks of the treatment period was 1.3 for SYMPROIC vs. 0.7 for placebo (difference 0.6, 95% CI 0.2, 0.9) in Study 1 and 1.8 for SYMPROIC vs. 1.1 for placebo (difference 0.7, 95% CI 0.3, 1.2) in Study 2.

SYMPROIC is contraindicated in:

• Patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation [see Warnings and Precautions (5.1)].
• Patients with a history of a hypersensitivity reaction to naldemedine. Reactions have included bronchospasm and rash [see Adverse Reactions (6.1)].

Serious and important adverse reactions described elsewhere in labeling include:

• Gastrointestinal perforation [see Warnings and Precautions (5.1)]
• Opioid withdrawal [see Warnings and Precautions (5.2)]

Table 3 includes drugs with clinically important drug interactions with SYMPROIC and instructions for preventing or managing the interaction.

Use of opioids induces slowing of gastrointestinal motility and transit. Antagonism of gastrointestinal mu-opioid receptors by naldemedine inhibits opioid-induced delay of gastrointestinal transit time.

Clusters of 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 [see Adverse Reactions (6.1)].

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.

The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naldemedine has not been evaluated. Avoid use of SYMPROIC in patients with severe hepatic impairment. No dose adjustment of SYMPROIC is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)].

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.

Naldemedine is an opioid antagonist with binding affinities for mu-, delta-, and kappa-opioid receptors. Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids.

Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB). Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Based on these properties, the CNS penetration of naldemedine is expected to be negligible at the recommended dose levels, limiting the potential for interference with centrally-mediated opioid analgesia.

• Gastrointestinal perforation: Consider the overall risk benefit in patients with known or suspected lesions of the GI tract. Monitor for severe, persistent, or worsening abdominal pain; discontinue if development of symptoms (5.1)
• Opioid withdrawal: Consider the overall risk benefit in patients with disruptions to the blood-brain barrier. Monitor symptoms of opioid withdrawal (5.2)

Administration ( 2.1 ):

• 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
• Discontinue SYMPROIC if treatment with the opioid pain medication is also discontinued

Dosage ( 2.2 ):

• In adults, the recommended dosage is 0.2 mg once daily with or without food

Tablets: 0.2 mg naldemedine; supplied as yellow, round, film-coated, debossed with Shionogi marking above the identifier code 222 on one side and 0.2 on the other side.

The following adverse reactions have been identified during post-approval use of SYMPROIC. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders: Gastrointestinal perforation [see Warnings and Precautions (5.1) ].

• Pregnancy: May precipitate opioid withdrawal in a fetus (8.1)
• Lactation: Discontinue drug or breastfeeding taking into consideration importance of drug to mother (8.2)
• Hepatic Impairment: Avoid in severe impairment (8.6)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to SYMPROIC in 1163 patients in clinical trials, including 487 patients with exposures greater than six months and 203 patients with exposures of 12 months.

The following safety data are derived from three double-blind, placebo-controlled trials in patients with OIC and chronic non-cancer pain: two 12-week studies (Studies 1 and 2) and one 52-week study (Study 3) [see Clinical Studies (14)].

In Studies 1 and 2, patients on laxatives were required to discontinue their use prior to study enrollment. All patients were restricted to bisacodyl rescue treatment during the study. In Study 3, approximately 60% of patients in both treatment groups were on a laxative regimen at baseline; patients were allowed to continue using their laxative regimen throughout the study duration. The safety profile of SYMPROIC relative to placebo was similar regardless of laxative use.

Tables 1 and 2 list common adverse reactions occurring in at least 2% of patients receiving SYMPROIC and at an incidence greater than placebo. Table 1 shows pooled 12-week data from Studies 1 and 2. Table 2 shows 12-week data from Study 3.

Adverse reactions up to 12 months in Study 3 are similar to those listed in Tables 1 and 2 (diarrhea: 11% vs. 5%, abdominal pain: 8% vs. 3%, and nausea: 8% vs. 6% for SYMPROIC and placebo, respectively).

Cases of gastrointestinal (GI) perforation have been reported with use of another peripherally acting opioid antagonist, including SYMPROIC. Postmarketing cases of GI perforation, including fatal cases, were reported when SYMPROIC was used in patients at risk of GI perforation (e.g., GI cancer, past GI surgery, diverticulitis, chemotherapy/radiation). SYMPROIC is contraindicated in patients with known or suspected gastrointestinal obstruction or in patients at risk of recurrent obstruction. Take into account the overall risk-benefit profile when using SYMPROIC in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue SYMPROIC in patients who develop this symptom.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

SYMPROIC is supplied as 0.2 mg naldemedine tablets as follows:

• bottle of 30 tablets - NDC 59385-041-30

7 Tablets

Each tablet contains 0.2 mg of naldemedine

(equivalent to 0.26 mg of naldemedine tosylate).

Usual adult dosage: See package insert.

Store at 20°C to 25°C (68°F to 77°F).

Mfd. for BioDelivery Sciences International, Inc.

Raleigh, NC 27612

Symproic^®

(naldemedine) tablets

0.2 mg

NDC 59385-041-07   Rx ONLY

Keep out of reach of children.

PHYSICIAN SAMPLES NOT FOR SALE

319623 04/19 SYM-0001.1b

DAY 1

DAY 2

DAY 3

DAY 4

DAY 5

DAY 6

DAY 7

LOT:

EXP:

NDC 59385-041-07

7 Tablets

Dosage: Take 1 tablet

once daily

Each tablet contains 0.2 mg of

naldemedine (equivalent to

0.26 mg of naldemedine tosylate).

Please see the included

Prescribing Information.

Keep out of reach of children.

Dispense the enclosed Medication Guide

to each patient.

Symproic^®

(naldemedine) tablets

0.2 mg

PHYSICIAN SAMPLES NOT FOR SALE

FOR ORAL USE ONLY

Rx ONLY

NDC 59385-041-30

Rx ONLY

30 Tablets

Symproic^®

(naldemedine) tablets

0.2 mg

Dispense the enclosed Medication Guide

to each patient.

Collegium_®

PHARMACEUTICAL

© 2023 Collegium Pharmaceutical, Inc.

Stoughton, MA 02072