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Naloxegol

Pronunciation

(nal OX ee gol)

Index Terms

  • Naloxegol Oxalate
  • NKTR-118

Dosage Forms

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

Tablet, Oral:

Movantik: 12.5 mg, 25 mg

Brand Names: U.S.

  • Movantik

Pharmacologic Category

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

Pharmacology

Naloxegol is a mu-opioid receptor antagonist. It is composed of naloxone conjugated with a polyethylene glycol polymer, which limits its ability to cross the blood-brain barrier. When administered at the recommended dose, naloxegol functions peripherally in tissues such as the GI tract, thereby decreasing the constipation associated with opioids (Webster, 2013).

Absorption

Rapid. With a high-fat meal, Cmax and AUC increased by 30% and 45%, respectively

Distribution

Vd: 968 to 2,140 L

Metabolism

Hepatic via CYP3A (primarily). Data suggests no major metabolites. Minor metabolites formed via N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain.

Excretion

Feces (68%; ~16% as unchanged drug); Urine (16%; <6% as unchanged drug)

Time to Peak

<2 hours; in majority of subjects, a secondary Cmax occurs ~0.4 to 3 hours after the first Cmax

Half-Life Elimination

6 to 11 hours

Protein Binding

~4.2%

Special Populations: Renal Function Impairment

In a pharmacokinetic study, most patients with renal impairment had similar pharmacokinetics to those with normal renal function. However, some patients with renal impairment demonstrated higher naloxegol exposures (up to 10- fold) compared with the control group when administered a 25 mg single oral dose; reason for these high exposures is unknown. Patients with ESRD on hemodialysis had similar plasma concentrations to those with normal renal function, when naloxegol was given either pre- or posthemodialysis (Bui, 2014)

Special Populations: Hepatic Function Impairment

After administration of a single 25 mg oral dose, slight decreases in AUC of naloxegol were observed in subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B) compared with subjects with normal hepatic function.

Special Populations: Elderly

The mean Cmax,ss and AUCtau,ss values seen in elderly healthy Japanese subjects were approximately 45% and 54% greater than those obtained in young healthy subjects following multiple daily doses of naloxegol (25 mg).

Special Populations: Race

Caucasian subjects exhibited approximately 20% higher naloxegol AUC compared with other races.

Use: Labeled Indications

Opioid-induced constipation: Treatment of opioid-induced constipation (OIC) in adult patients with chronic noncancer pain.

Contraindications

Serious or severe hypersensitivity reaction to naloxegol or any component of the formulation; known or suspected GI obstruction or at increased risk of recurrent obstruction; concomitant use with strong CYP3A4 inhibitors (eg, clarithromycin, ketoconazole)

Dosing: Adult

Note: Discontinue all maintenance laxative therapy prior to use; may reintroduce laxatives as needed if suboptimal response to naloxegol after 3 days. Alteration in analgesic dosing regimen prior to initiating naloxegol is not required.

Opioid-induced constipation: Oral: 25 mg once daily in the morning on an empty stomach. If not tolerated, reduce dose to 12.5 mg once daily. Discontinue treatment if opioid pain medication is discontinued.

Dosing adjustment with concomitant medications:

Weak CYP3A4 inhibitors (eg, quinidine, cimetidine):

US labeling: No dosage adjustment necessary

Canadian labeling: Initial: 12.5 mg once daily

Moderate CYP3A4 Inhibitors (eg, diltiazem, erythromycin, verapamil): Avoid concomitant use. If concurrent use is unavoidable, reduce dose of naloxegol to 12.5 mg once daily and monitor for adverse reactions.

Strong CYP3A4 inhibitors (eg, clarithromycin, ketoconazole): Concomitant use is contraindicated.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥60 mL/minute: No dosage adjustment necessary.

CrCl <60 mL/minute: Initial dose 12.5 mg once daily; if well tolerated but opioid-induced constipation symptoms continue, may increase to 25 mg once daily, taking into consideration the potential for markedly increased exposures in some patients with renal impairment and the increased risk of adverse reactions with higher exposures.

End-stage renal disease (ESRD): Initial: 12.5 mg once daily; if well tolerated but opioid-induced constipation symptoms continue, may increase to 25 mg once daily, taking into consideration the potential for markedly increased exposures in some patients with renal impairment and the increased risk of adverse reactions with higher exposures.

Dialysis: Not readily dialyzed (ineffective).

Dosing: Hepatic Impairment

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

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

Administration

Oral: Administer naloxegol on an empty stomach at least 1 hour prior to or 2 hours after the first meal of the day. Swallow tablets whole, do not crush or chew. Avoid consumption of grapefruit or grapefruit juice during treatment.

Dietary Considerations

Take on an empty stomach. Avoid grapefruit or grapefruit juice.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

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

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Naloxegol. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Naloxegol. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Naloxegol. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Naloxegol. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

>10%: Gastrointestinal: Abdominal pain (12% to 21%)

1% to 10%:

Central nervous system: Headache (4%)

Dermatologic: Hyperhidrosis (≤3%)

Gastrointestinal: Diarrhea (6% to 9%), nausea (7% to 8%), flatulence (3% to 6%), vomiting (5%)

<1% (Limited to important or life-threatening):Anxiety, arthritis, back pain, chills, gastrointestinal perforation, irritability, joint pain, yawning

Warnings/Precautions

Concerns related to adverse reactions:

• GI perforation: GI perforation has been reported with use of another peripherally acting opioid antagonist (ie, methylnaltrexone) in patients with reduced wall integrity of the GI tract (eg, peptic ulcer disease, Ogilvie syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies, peritoneal metastases). Consider the overall risk-benefit profile when using naloxegol in patients with these conditions or other conditions which might result in impaired integrity of the GI tract wall (eg, Crohn disease). Monitor for development of severe, persistent or worsening abdominal pain; discontinue naloxegol if this occurs. Use is contraindicated in patients with known or suspected GI obstruction or at increased risk of recurrent obstruction.

• Withdrawal: Symptoms consistent with opioid withdrawal (eg, hyperhidrosis, chills, abdominal pain, anxiety, irritability) have occurred. In clinical trials, patients receiving methadone for pain management were observed to have a higher frequency of GI adverse reactions that may have been related to opioid withdrawal than patients receiving other opioids. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Consider the overall risk-benefit profile when using naloxegol in such patients. Monitor for symptoms of opioid withdrawal in such patients.

Disease-related concerns:

• Hepatic impairment: Avoid use in patients with severe hepatic impairment.

• Renal impairment: Dosage reduction recommended in patients with CrCl <60 mL/minute.

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: Discontinue naloxegol if opioids are discontinued.

Monitoring Parameters

Symptoms of GI obstruction (eg, severe, persistent, or worsening abdominal pain); symptoms of opioid withdrawal (eg, chills, diaphoresis, anxiety, irritability, changes in blood pressure or heart rate).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. However, exposure during pregnancy may potentiate opioid withdrawal in the fetus. Due to the potential risk of opioid withdrawal in the fetus, the Canadian labeling does not recommend use 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?)

• Patient may experience flatulence or headache. Have patient report immediately to prescriber severe diarrhea; severe abdominal edema; severe 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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