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Naldemedine

Generic name: naldemedine systemic

Brand names: Symproic

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Symproic: 0.2 mg

Pharmacology

Mechanism of Action

Opioid antagonist that blocks opioid binding at the mu, delta, and kappa receptors; functions as a peripherally acting mu-opioid receptor antagonist, including actions on the GI tract to inhibit the delay in GI transit time, thereby decreasing the constipating effects of opioids.

Pharmacokinetics/Pharmacodynamics

Distribution

Vd: 155 L

Metabolism

CYP3A to nor-naldemedine (major); UGT1A3 to naldemedine 3-G (minor); also undergoes cleavage in the GI tract to form benzamidine and naldemedine carboxylic acid.

Excretion

Urine (57%; 16% to 18% as unchanged drug; 32% as benzamidine metabolite); feces (35%; 20% as benzamidine metabolite).

Time to Peak

0.75 hours; 2.5 hours (with food)

Half-Life Elimination

11 hours

Protein Binding

93% to 94%

Use: Labeled Indications

Opioid-induced constipation: Treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (eg, weekly) opioid dosage escalation.

Contraindications

Hypersensitivity to naldemedine or any component of the formulation; GI obstruction (known or suspected) or at increased risk of recurrent obstruction.

Dosage and Administration

Dosing: Adult

Opioid-induced constipation: Oral: 0.2 mg once daily. Discontinue treatment if opioid pain medication is discontinued.

Dosing: Geriatric

Refer to adult dosing.

Administration

Administer without regard to meals.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Naldemedine. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Naldemedine. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Naldemedine. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Naldemedine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Opioid Antagonists: May enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Naldemedine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Gastrointestinal: Abdominal pain (8%), diarrhea (7%)

1% to 10%:

Gastrointestinal: Nausea (4%), vomiting (3%), gastroenteritis (2%)

<1%, postmarketing, and/or case reports: Hypersensitivity reaction

Warnings/Precautions

Concerns related to adverse effects:

  • GI perforation: GI perforation has been reported with use of another peripherally acting opioid antagonist in patients with advanced illnesses associated with impaired structural integrity of the GI wall (eg, Ogilvie syndrome, peptic ulcer disease, diverticular disease, infiltrative GI tract malignancies, peritoneal metastases). Use with caution in these patients or in patients with other conditions that may result in impaired integrity of the GI wall (eg, Crohn disease). Monitor for development of severe, persistent or worsening abdominal pain; discontinue therapy if this occurs. Use is contraindicated in patients with known or suspected GI obstruction or in patients at increased risk of recurrent GI obstruction.
  • Opioid withdrawal: May precipitate symptoms of opioid withdrawal (eg, abdominal pain, chills, diarrhea, hyperhidrosis, nausea, vomiting). Use with caution in patients with disruptions to the blood-brain barrier; may increase the risk for opioid withdrawal and/or reduced analgesia. Monitor for symptoms of opioid withdrawal in such patients.

Disease-related concerns:

  • Hepatic impairment: Avoid use in severe impairment (Child-Pugh class C).

Concurrent drug therapy issues:

  • Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

  • Appropriate use: Efficacy has been established in patients who have taken opioids for ≥4 weeks; patients receiving opioids for <4 weeks may be less responsive to naldemedine.

Monitoring Parameters

Symptoms of GI perforation (eg, severe, persistent, or worsening abdominal pain); symptoms of opioid withdrawal.

Pregnancy

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Based on animal data, naldemedine may cross the placenta and cause opioid withdrawal in the fetus if administered during pregnancy.

Patient Education

What is this drug used for?

  • It is used to treat constipation caused by some pain drugs.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Severe or persistent diarrhea
  • Severe or persistent abdominal pain
  • Vomiting blood
  • Nausea
  • Vomiting
  • Black, tarry, or bloody stools
  • Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated February 5, 2020.