sign in sign up
<<
Home , Alvimopan, Naldemedine

PDL REVIEW

Proprietary Name: Symproic® Common Name: PDL Category: GI, ‐ IBS‐OIC

Comparable Products Preferred Drug List Status Amitiza Non‐ Preferred with Conditions Movantik Non‐Preferred with Conditions

Summary

Pharmacology/Usage: Naldemedine, the active ingredient of Symproic®, is an antagonist with binding affinities for mu‐, delta‐ and kappa‐opioid receptors. It functions as a peripherally‐acting mu‐ antagonist in tissues, such as the GI tract, thus decreasing the constipating effects of . Naldemedine is a derivative of to which a side chain has been added that reduces its ability to cross the blood‐brain barrier. It is also a substrate of P‐gp efflux transporter. Overall, per its properties, the CNS penetration of naldemedine is expected to be negligible at the recommended dose levels, thus limiting the potential for interference with centrally‐mediated opioid analgesia.

Indications: 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.

There is no pregnancy category for this product; however, the risk summary indicates that there are no available data in pregnant women to inform the drug‐associated risk of major birth defects and miscarriage. Naldemedine crosses the placenta. There is a potential for 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. The safety and efficacy of use in the pediatric population have not been established.

Dosage Forms: Film‐coated Tablets: 0.2mg

Recommended Dosage: Alteration of dosing regimen prior to starting Symproic® is not required. Those receiving opioids for less than 4 weeks may be less responsive to Symproic®, and treatment with Symproic® should be discontinued if treatment with the opioid pain medication is also discontinued.

Take one tablet PO QD, with or without food. Dose adjustments are not required with renal impairment or with mild or moderate hepatic impairment. It is recommended to avoid use in patients with severe hepatic impairment.

Drug Interactions: The concomitant use of Symproic® with strong CYP3A inducers (e.g. rifampin, carbamazepine, phenytoin, St. John’s Wort) should be avoided. The concomitant use of Symproic® with another

1 should be avoided. It is recommended to monitor for potential naldemedine‐related adverse reactions if use Symproic® concomitantly with moderate (e.g. fluconazole, atazanavir, aprepitant, , erythromycin) and strong (e.g. , , , ritonavir, saquinavir) CYP3A inhibitors. It is also recommended to monitor for potential naldemedine‐related adverse reactions if use Symproic® concomitantly with P‐gp inhibitors (e.g. , captopril, cyclosporine, quercetin, , ).

Common Adverse Drug Reactions: Listed % incidence for adverse drug reactions= reported % incidence for drug (Symproic®) minus reported % incidence for placebo. Please note that an incidence of 0% means the incidence was the same as or that the active drug was less than placebo. The most frequently reported adverse events included abdominal pain (6%), diarrhea (5%), (2%), and (1%).

Cases of gastrointestinal perforation have been reported with the 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 (e.g. peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative GI tract malignancies, or peritoneal metastases). Monitor for the development of severe, persistent, or worsening of abdominal pain, and discontinue Symproic® in patients who develop this symptom.

Symptoms consistent with opioid withdrawal have occurred in patients treated with Symproic®, such as hyperhidrosis, chills, increased lacrimation, feeling cold, nausea, and vomiting. Patients having disruptions to the blood‐brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Monitor for symptoms of opioid withdrawal in such patients.

Contraindications: With known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation; With a history of hypersensitivity reaction to the active ingredient.

Manufacturer: LP

Analysis: The safety and efficacy of Symproic® were assessed in two replicate, 12‐week, randomized, double‐ blind, placebo‐controlled studies where Symproic® was used without in adults with opioid induced constipation (OIC) and chronic non‐cancer pain receiving a stable opioid equivalent daily dose of at least 30mg for at least 4 weeks before enrollment (N=1100). Adults with evidence of significant structural abnormalities of the GI tract were not enrolled in these studies. In both studies, adults had to either be not using laxatives or willing to discontinue use at the time of screening and willing to use only the provided rescue laxatives.

OIC was confirmed in both studies during a 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 1 or more of the following, including straining; hard or lumpy stools; having a sensation of incomplete evacuation; and have a sensation of anorectal obstruction/blockage. A SBM was defined as a bowel movement without rescue laxative taken within the past 24 hours. was allowed as rescue laxative during the screening and treatment periods if patients had not had a bowel movement for 72 hours, and patients were allowed one‐time use of an if after 24 hours of taking bisacodyl they still hadn’t had a bowel movement.

The efficacy of Symproic® was assessed in study 1 and 2 using a responder analysis. A responder was defined as a patient who had at least 3 SMBs per week and a change from baseline of at least 1 SBM per week for at least 9 of the 12 weeks and 3 out of the last 4 weeks in both studies. Results can be seen in the table below, which was adapted from the prescribing information.

Study 1 Study 2 Symproic® Placebo Treatment Symproic® Placebo Treatment (N=273) (N=272) difference (N=276) (N=274) difference Responder 130 (48%) 94 (35%) 13% 145 (53%) 92 (34%) 19%

2 Study 1 Study 2 Symproic® Placebo Treatment Symproic® Placebo Treatment (N=273) (N=272) difference (N=276) (N=274) difference p‐value p=0.0020 p˂0.0001

In both studies, the mean increase in frequency of SBMs per week from baseline to the last 2 weeks of the 12‐ week period was 3.1 for Symproic® vs 2.0 for placebo and 3.3 for Symproic® vs 2.1 for placebo, 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 in study 1 and 3.7 for Symproic® vs 1.6 for placebo in study 2. 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 in study 1 and 1.8 for Symproic® vs 1.1 for placebo in study 2.

A complete SBM (CSBM) was defined as a SBM that was associated with a sense of complete evacuation. The mean increase in the frequency of CSBMs per week from baseline to the last 2 weeks of the 12‐week period was 2.3 for Symproic® vs 1.5 for placebo in study 1 and 2.6 for Symproic® vs 1.6 for placebo in study 2.

Place in Therapy: Symproic® is an opioid antagonist indicated for the treatment of opioid‐induced constipation (OIC) in adults 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. Based on certain properties, the CNS penetration is expected to be negligible at recommended dosing, thus limiting the potential for interference with centrally‐mediated opioid analgesia. Use is contraindicated with known or suspected gastrointestinal obstruction and those at increased risk of recurrent obstruction. Symproic® should not be used concomitantly with strong CYP3A inducers or with other opioid antagonists.

While a double‐blind, head‐to‐head comparator study was not found, a mixed treatment comparison network meta‐analysis by Sridharan et al2 published in 2017 that included 21 randomized controlled trials was found that assessed the available interventions for the treatment of opioid‐induced constipation. The primary outcome was the number of patients with rescue‐free bowel movement (RFBM), which was the number of patients with bowel movements without any laxatives in the prior 24 hours. Interventions assessed included , , naldemedine, , , senna, and oral and subcutaneous . Results suggested all interventions significantly improved the RFBM compared to placebo, but SC methylnaltrexone had the highest odds ratio for the inventions (7.02). It performed better than lubiprostone, naloxegol, alvimopan, and oral methylnaltrexone. The OR for naldemedine as compared with placebo was 5.77.

There is no evidence at this time that Symproic® is safer or more effective than the currently available medications. It is therefore recommended that Symproic® remain non‐preferred to ensure it is used in clinically appropriate situations.

PDL Placement: † Preferred : Non‐Preferred with Conditions

References

1 Symproic [package insert]. Stamford, CT: Purdue Pharma; 2017. 2 Sridharan K, Sivaramakrishnan G. for treating opioid‐induced constipation: A mixed treatment comparison network meta‐analysis of randomized controlled clinical trials. J Pain Symptom Manage. 2017. [Epub ahead of print].

Prepared By: IME Date: 02/16/2018 Property of IME and may not be reproduced without permission 3