Naldemedine

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. SYMPROIC is an opioid antagonist 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 ( 1 )

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 2.1 Administration 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.

2.2 Adult Dosage The recommended dosage of SYMPROIC is 0.2 mg orally 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. Tablets: 0.2 mg naldemedine ( 3 )

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) ] . Patients with known or suspected gastrointestinal obstruction or at increased risk of recurrent obstruction ( 4 , 5.1 ) Patients with a history of a hypersensitivity reaction to naldemedine ( 6.1 )

5 WARNINGS AND PRECAUTIONS 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 )

5.1 Gastrointestinal Perforation 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.

5.2 Opioid Withdrawal 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.

Table 3 includes drugs with clinically important drug interactions with SYMPROIC and instructions for preventing or managing the interaction. Table 3: Clinically Relevant Interactions Affecting Naldemedine When Co-Administered with Other Drugs Strong CYP3A Inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) Clinical Impact Significant decrease in plasma naldemedine concentrations, which may reduce efficacy [see Clinical Pharmacology (12.3) ] Intervention Avoid use of SYMPROIC with strong CYP3A inducers. Other Opioid Antagonists Clinical Impact Potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal. Intervention Avoid use of SYMPROIC with another opioid antagonist. Moderate (e.g., fluconazole, atazanavir, aprepitant, diltiazem, erythromycin) and Strong (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir, saquinavir) CYP3A Inhibitors Clinical Impact Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3) ] Intervention Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1) ] . P-glycoprotein (P-gp) Inhibitors (e.g., amiodarone, captopril, cyclosporine, quercetin, quinidine, verapamil) Clinical Impact Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3) ] Intervention Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1) ] . Strong CYP3A inducers (e.g., rifampin) : Decreased naldemedine concentrations; avoid concomitant use ( 7 ) Other opioid antagonists : Potential for additive effect and increased risk of opioid withdrawal; avoid concomitant use ( 7 ) Moderate (e.g., fluconazole) and strong (e.g., itraconazole) CYP3A4 inhibitors : Increased naldemedine concentrations; monitor for adverse reactions ( 7 ) P-gp inhibitors (e.g., cyclosporine) : Monitor for adverse reactions ( 7 )

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) ] Most common adverse reactions (≥2%) are: abdominal pain, diarrhea, nausea and gastroenteritis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioDelivery Sciences International, Inc. at 1-800-469-0261 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience 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. Table 1: Common Adverse Reactions Adverse reactions occurring in at least 2% of patients receiving SYMPROIC and at an incidence greater than placebo in Patients with OIC and Chronic Non-Cancer Pain (12-week data from Studies 1 and 2) Adverse Reaction SYMPROIC 0.2 mg once daily N=542 Placebo N=546 Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain. 8% 2% Diarrhea 7% 2% Nausea 4% 2% Gastroenteritis 2% 1% Table 2: Common Adverse Reactions Adverse reactions occurring in at least 2% of patients receiving SYMPROIC and at an incidence greater than placebo in Patients with OIC and Chronic Non-Cancer Pain (12-week data from Study 3) Adverse Reaction SYMPROIC 0.2 mg once daily N=621 Placebo N=619 Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper. 11% 5% Diarrhea 7% 3% Nausea 6% 5% Vomiting 3% 2% Gastroenteritis 3% 1% 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). 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. Less Common Adverse Reactions: Two patients developed symptoms of hypersensitivity following a single dose of SYMPROIC. One patient reported bronchospasm and another rash.

6.2 Postmarketing Experience 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) ].

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) ] .

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 )

8.1 Pregnancy Risk Summary There are no available data with naldemedine in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. There is a potential for opioid withdrawal in a fetus when SYMPROIC is used in pregnant women [see Clinical Considerations ]. SYMPROIC should be used during pregnancy only if the potential benefit justifies the potential risk. In a rat embryo-fetal development study following oral administration of naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 23,000 times the human area under the plasma-concentration time curve (AUC) at the recommended human dose of 0.2 mg/day, no developmental abnormalities were observed. In rabbits, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 226 times the human AUC at the recommended human dose of 0.2 mg/day [see Data ]. No effects on pre- and postnatal development were observed in rats at exposures 12 times human exposures at the recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Naldemedine crosses the placenta, and may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. Data Animal Data In rats, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses up to 1000 mg/kg/day (approximately 23,000 times the human exposures (AUC) at the recommended human dose). In rabbits, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses up to 100 mg/kg/day (approximately 226 times the human exposures (AUC) at the recommended human dose). At 400 mg/kg/day (approximately 844 times the human exposures (AUC) at the recommended human dose), effects in maternal animals included body weight loss/decreased body weight gain and food consumption, fetal loss, and premature delivery. Decreased fetal body weights at this dose may be related to the maternal toxicity observed. In the pre- and postnatal development study, pregnant rats were administered naldemedine at oral doses up to 1000 mg/kg/day from gestation day 7 through lactation day 20. No effects on pre- and postnatal development were observed in rats at 1 mg/kg/day (approximately 12 times the human exposures (AUC) at the recommended human dose). A single dam died at parturition at 1000 mg/kg/day, and decreased body weights/body weight gain and food consumption, poor nursing, and total litter loss were noted at 30 and 1000 mg/kg/day (approximately 626 and 17,000 times the human exposures (AUC) at the recommended human dose, respectively). Decreases in the offspring viability index on Day 4 after birth were noted at 30 and 1000 mg/kg/day, and low body weights and delayed pinna unfolding in pups were noted at 1000 mg/kg/day.

8.2 Lactation Risk Summary There is no information regarding the presence of naldemedine in human milk, the effects on the breastfed infant, or the effects on milk production. Naldemedine was present in the milk of rats [see Data ] . 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. If drug is discontinued in order to minimize drug exposure to a breastfed infant, advise women that breastfeeding may be resumed 3 days after the final dose of SYMPROIC. Data Drug-related radioactivity was transferred into milk of lactating rats following a single oral dose of 1 mg/kg [carbonyl- 14 C]-naldemedine.

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

8.5 Geriatric Use 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) ].

Risk Summary There are no available data with naldemedine in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. There is a potential for opioid withdrawal in a fetus when SYMPROIC is used in pregnant women [see Clinical Considerations ]. SYMPROIC should be used during pregnancy only if the potential benefit justifies the potential risk. In a rat embryo-fetal development study following oral administration of naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 23,000 times the human area under the plasma-concentration time curve (AUC) at the recommended human dose of 0.2 mg/day, no developmental abnormalities were observed. In rabbits, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 226 times the human AUC at the recommended human dose of 0.2 mg/day [see Data ]. No effects on pre- and postnatal development were observed in rats at exposures 12 times human exposures at the recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Naldemedine crosses the placenta, and may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. Data Animal Data In rats, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses up to 1000 mg/kg/day (approximately 23,000 times the human exposures (AUC) at the recommended human dose). In rabbits, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses up to 100 mg/kg/day (approximately 226 times the human exposures (AUC) at the recommended human dose). At 400 mg/kg/day (approximately 844 times the human exposures (AUC) at the recommended human dose), effects in maternal animals included body weight loss/decreased body weight gain and food consumption, fetal loss, and premature delivery. Decreased fetal body weights at this dose may be related to the maternal toxicity observed. In the pre- and postnatal development study, pregnant rats were administered naldemedine at oral doses up to 1000 mg/kg/day from gestation day 7 through lactation day 20. No effects on pre- and postnatal development were observed in rats at 1 mg/kg/day (approximately 12 times the human exposures (AUC) at the recommended human dose). A single dam died at parturition at 1000 mg/kg/day, and decreased body weights/body weight gain and food consumption, poor nursing, and total litter loss were noted at 30 and 1000 mg/kg/day (approximately 626 and 17,000 times the human exposures (AUC) at the recommended human dose, respectively). Decreases in the offspring viability index on Day 4 after birth were noted at 30 and 1000 mg/kg/day, and low body weights and delayed pinna unfolding in pups were noted at 1000 mg/kg/day.

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) ].

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 C 32 H 34 N 4 O 6 ∙C 7 H 8 O 3 S 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. Chemical Structure

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.

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. Effect on Cardiac Repolarization At a dose up to 5 times the recommended dose, SYMPROIC does not prolong the QT interval to any clinically relevant extent.

, Mutagenesis, Impairment of Fertility Carcinogenesis In 2-year carcinogenicity studies, there were no drug-related neoplastic findings following oral administration of naldemedine to mice and rats at doses up to 100 mg/kg/day (approximately 17,500 and 6,300 times the human exposures (AUC) at the recommended human dose, respectively). Mutagenesis Naldemedine was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, a chromosomal aberration assay with cultured Chinese hamster lung cells, or an in vivo micronucleus assay with rat bone marrow cells. Impairment of Fertility Naldemedine was found to have no effect on fertility or reproductive performance in male and female rats at oral doses up to 1000 mg/kg/day (approximately 17,000 times the human exposures (AUC) at the recommended human dose). In female rats, prolongation of diestrous phase was noted at 10 mg/kg/day (approximately 179 times the human exposures (AUC) at the recommended human dose).

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Advise patients to discontinue SYMPROIC if treatment with the opioid pain medication is also discontinued. Gastrointestinal Perforation Advise patients to discontinue SYMPROIC and to promptly seek medical attention if they develop unusually severe, persistent or worsening abdominal pain [see Warnings and Precautions (5.1) ] . Opioid Withdrawal Advise patients that clusters of symptoms consistent with opioid withdrawal may occur while taking SYMPROIC and to contact their healthcare provider if these symptoms occur [see Warnings and Precautions (5.2) ] . Pregnancy Advise females of reproductive potential, who become pregnant or are planning to become pregnant, that the use of SYMPROIC during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood-brain barrier [see Use in Specific Populations (8.1) ] . Lactation Advise women that breastfeeding is not recommended during treatment with SYMPROIC and for 3 days after the final dose [see Use in Specific Populations (8.2) ] .

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].