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.

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.

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.

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)].

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.

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 supplied as 0.2 mg naldemedine tablets as follows:

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

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

SYMPROIC is a registered trademark of Shionogi & Co., Ltd.
Manufactured for: BioDelivery Sciences International, Inc. Raleigh, NC 27612
SYM-001-PI-MAY2020

NDC 59385-041-30
Rx ONLY
30 Tablets

Symproic®
(naldemedine) tablets
0.2 mg

Dispense the enclosed Medication Guide
to each patient.

biodelivery
SCIENCES

© 2019 BioDelivery Sciences International, Inc.
Raleigh, NC 27612

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