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Naldemedine

Pronunciation

(nal DEM e deen)

Index Terms

  • Naldemedine Tosylate
  • Symproic

Dosage Forms

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

Tablet, Oral:

Symproic: 0.2 mg

Brand Names: U.S.

  • Symproic

Pharmacologic Category

  • Gastrointestinal Agent, Miscellaneous
  • Opioid Antagonist, Peripherally-Acting

Pharmacology

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.

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.

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.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh classes A and B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): Avoid use (has not been studied).

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

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

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

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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 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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber severe or persistent diarrhea; severe or persistent abdominal pain; vomiting blood; nausea; vomiting; or black, tarry, or bloody stools (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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