Symproic Drug Information

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.

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

Adult Dosage

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

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 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). 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.

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. 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.

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.

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 Increase in plasma naldemedine concentrations Intervention Monitor for potential naldemedine-related adverse reactions.

P-glycoprotein (P-gp) Inhibitors (e.g., amiodarone, captopril, cyclosporine, quercetin, quinidine, verapamil) Clinical Impact Increase in plasma naldemedine concentrations Intervention Monitor for potential naldemedine-related adverse reactions. Strong CYP3A inducers (e.g., rifampin): Decreased naldemedine concentrations; avoid concomitant use Other opioid antagonists: Potential for additive effect and increased risk of opioid withdrawal; avoid concomitant use Moderate (e.g., fluconazole) and strong (e.g., itraconazole) CYP3A4 inhibitors: Increased naldemedine concentrations; monitor for adverse reactions P-gp inhibitors (e.g., cyclosporine): Monitor for adverse reactions

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. 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. 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 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). 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. 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).

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

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. Patients with a history of a hypersensitivity reaction to naldemedine. Reactions have included bronchospasm and rash.

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. 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.