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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

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

AUC was approximately 20% lower in blacks and Cmax was approximately 10% lower and 30% higher in blacks and Asians, respectively.

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

Serious or severe hypersensitivity reaction to naloxegol or any component of the formulation; GI obstruction (known or suspected) 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. If not tolerated, reduce dose to 12.5 mg once daily. Discontinue treatment if opioid pain medication is discontinued.

Dosing adjustment with concomitant medications:

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 and end-stage renal disease (ESRD): 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.

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

Avoid consumption of grapefruit or grapefruit juice during treatment.

Oral: Administer 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 chew. For patients unable to swallow tablet whole, may crush the tablet into a powder and mix with 120 mL of water, and drink immediately; refill glass with 120 mL water, stir and drink.

Nasogastric (NG) feeding tube: Flush the NG tube with 30 mL water using a 60 mL syringe. Crush tablet into a powder and mix with ~60 mL of water; draw up the mixture using the 60 mL syringe and administer through the NG tube. Rinse the same container used to prepare the dose with ~60 mL of water; draw up the water using the same syringe and use all of the water to flush the NG tube and any remaining medicine.

Dietary Considerations

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 (High risk with Inducers). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. 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 (High risk with Inhibitors). Monitor therapy

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

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 (High risk with Inducers). 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:

• Gastrointestinal effects: Severe abdominal pain and/or diarrhea have been reported; may result in hospitalization. Most cases of severe abdominal pain were due to the 25 mg dosage and generally occurred within a few days of initiation of therapy. Monitor for development of abdominal pain and/or diarrhea; discontinue therapy if this occurs. May consider restarting at lower dose.

• GI perforation: GI perforation has been reported with use of another peripherally acting opioid antagonist (ie, methylnaltrexone) in patients with localized or diffuse reduction of structural wall integrity of the GI tract (eg, peptic ulcer disease, Ogilvie syndrome, diverticular disease, infiltrative GI tract malignancies, peritoneal metastases). Use with caution in these patients or in patients with other conditions that might result in impaired integrity of the GI tract 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 GI obstruction (known or suspected) or at increased risk of recurrent GI obstruction.

• Opioid withdrawal: Symptoms consistent with opioid withdrawal (eg, hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, yawning) have occurred. Use with caution in patients with disruptions to the blood-brain barrier; may increase the risk for opioid withdrawal or reduced analgesia. 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 adjustment 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: Patients receiving opioids for less than 4 weeks may be less responsive.

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.

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 or persistent 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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