Movantik (naloxegol oxalate)

Dosage of naloxegol oxalate is expressed in terms of naloxegol.

The recommended adult dosage of naloxegol for the management of opiate-induced constipation in patients with chronic non-cancer-related pain is 25 mg once daily in the morning. If patients cannot tolerate the 25-mg daily dosage, dosage of naloxegol may be reduced to 12.5 mg once daily in the morning.

If concomitant use of moderate cytochrome P-450 (CYP) 3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) is unavoidable, dosage of naloxegol should be reduced to 12.5 mg once daily, and the patient should be monitored for adverse effects. (See Drug Interactions.)

Naloxegol oxalate is administered orally on an empty stomach at least 1 hour before or 2 hours after the first meal of the day. For patients who have cannot swallow naloxegol oxalate tablets whole, the tablet may be crushed to a powder and mixed with 120 mL of water in a glass; the resulting mixture should be stirred and then swallowed immediately. To ensure consumption of the entire dose, the glass should be rinsed with 120 mL of water; the resulting mixture should be stirred and then swallowed immediately.

For administration through a nasogastric tube, the nasogastric tube should first be flushed with 30 mL of water using a 60-mL syringe. The tablet should then be crushed to a powder and mixed with approximately 60 mL of water in a container. The resulting mixture should be drawn up into the 60-mL syringe and administered through the nasogastric tube. To facilitate delivery of the entire dose, the container should be rinsed with approximately 60 mL of water, the mixture should be drawn up into the same syringe, and the entire contents of the syringe should be used to flush the nasogastric tube.

Plasma concentrations of naloxegol attained when a crushed naloxegol oxalate tablet is mixed in water and administered either orally or through a nasogastric tube are comparable to those attained following oral administration of an intact tablet of the drug.

No dosing information is available for this tab.

Naloxegol is metabolized principally by cytochrome P-450 (CYP) 3A isoenzymes and is a substrate, but not a clinically important inhibitor, of P-glycoprotein (P-gp). Naloxegol did not inhibit CYP 1A2, 2C9, 2C19, 2D6, or 3A4 nor substantially induce CYP 1A2, 2B6, or 3A4 in vitro at clinically relevant concentrations, and is not expected to alter metabolic clearance of drugs metabolized by these enzymes.

Naloxegol does not substantially inhibit breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1 or 3, organic cation transporter (OCT) 2, or organic anion transport protein (OATP) 1B1 or 1B3.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Naloxegol (> 12.5 Mg)/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of naloxegol.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 without a dosage adjustment of naloxegol may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1)

PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1)

PATIENT MANAGEMENT: The daily dose of naloxegol should be limited to 12.5 mg daily in patients taking moderate inhibitors of CYP3A4.(1) If concurrent use is deemed medically necessary, monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1)

DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) According to Physiologically-based-Pharmacokinetic (PBPK) models, erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is expected to increase the Cmax and AUC of naloxegol by 2.77-fold and 3.47-fold, respectively.(2) According to PBPK models, erythromycin at a dose of 400 mg QID is expected to increase the Cmax and AUC of naloxegol by 3.42-fold and 4.63-fold, respectively.(2) According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol by 2.4-fold and 2.81-fold, respectively.(2) According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol by 1.97-fold and 2.21-fold, respectively.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3,4)

Naloxegol/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of naloxegol.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1)

PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1)

PATIENT MANAGEMENT: The concurrent use of naloxegol and strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that concurrent administration with naloxegol is contraindicated during and two weeks after itraconazole treatment.(5) If concurrent use is deemed medically necessary, monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1)

DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Naloxegol (<= 12.5 Mg)/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of naloxegol.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 without a dosage adjustment of naloxegol may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1)

PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1)

PATIENT MANAGEMENT: Avoid the use of moderate inhibitors of CYP3A4 in patients who require therapy with naloxegol. If concurrent use cannot be avoided, the daily dose of naloxegol should be limited to 12.5 mg daily in patients taking moderate inhibitors of CYP3A4.(1) Monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1)

DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) According to Physiologically-based-Pharmacokinetic (PBPK) models, erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is expected to increase the Cmax and AUC of naloxegol by 2.77-fold and 3.47-fold, respectively.(2) According to PBPK models, erythromycin at a dose of 400 mg QID is expected to increase the Cmax and AUC of naloxegol by 3.42-fold and 4.63-fold, respectively.(2) According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol by 2.4-fold and 2.81-fold, respectively.(2) According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol by 1.97-fold and 2.21-fold, respectively.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3,4)

Naloxegol/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of naloxegol.(1)

CLINICAL EFFECTS: Concurrent use of a strong inducers of CYP3A4 may result in decreased levels and effectiveness of naloxegol.(1)

PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Concurrent use of a strong inducer of CYP3A4 with naloxegol is not recommended.(1) If concurrent use is warranted, monitor patients for signs of decreased naloxegol effectiveness, such as constipation. Patients may require additional laxative therapy.

DISCUSSION: Rifampin (600 mg daily for 13 days), a strong inducer of CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 75% and 89%, respectively.(2) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(1,3,4)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Naloxegol/Bevacizumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Both naloxegol and bevacizumab have been reported to cause gastrointestinal perforation.

CLINICAL EFFECTS: Concurrent use of bevacizumab may increase the risk of gastrointestinal perforation in patients receiving naloxegol.(1)

PREDISPOSING FACTORS: Patients with infiltrative gastrointestinal tract malignancy, recent gastrointestinal tract surgery, diverticular disease including diverticulitis, and/or ischemic colitis may be at increased risk of gastrointestinal perforation.(1)

PATIENT MANAGEMENT: Consider the risk-benefit profile when using naloxegol in patients on concurrent bevacizumab, especially if they have conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease). Monitor for the development of severe, persistent or worsening abdominal pain. Discontinue naloxegol in patients who develop gastrointestinal perforation.(1)

DISCUSSION: There are no published reports of gastrointestinal perforation with the combination of naloxegol and bevacizumab. The FDA Adverse Events Reporting System (FAERS) database contains one report of a 45 year old man with metastatic rectal cancer who developed small intestinal perforation while on naloxegol and bevacizumab.

Because of the potential for GI perforation, naloxegol is contraindicated in patients with known or suspected GI obstruction and in patients at increased risk for recurrent GI obstruction (see GI Perforation under Cautions: Warnings/Precautions).

Naloxegol is contraindicated in patients receiving potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) (e.g., clarithromycin, ketoconazole) because of the potential for increased exposure to naloxegol and precipitation of opiate withdrawal (see Drug Interactions).

Naloxegol also is contraindicated in patients with known serious or severe hypersensitivity reactions to the drug or any ingredient in the formulation.

• Gastrointestinal obstruction
• Lactation

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Opioid withdrawal symptoms

There are no moderate contraindications for this drug.

Adverse effects reported in 3% or more of patients receiving naloxegol 12.5 or 25 mg daily and at an incidence greater than that observed with placebo include abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, and hyperhidrosis.

Rare or Very Rare

• Angioedema
• Gastrointestinal perforation
• Opioid withdrawal symptoms
• Urticaria

More Frequent

• Acute abdominal pain
• Diarrhea
• Flatulence
• Headache disorder
• Nausea
• Vomiting

Less Frequent

• Hyperhidrosis

Rare or Very Rare

• Skin rash

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Safety and efficacy of naloxegol have not been established in pediatric patients.

Category C. (See Users Guide.)

Naloxegol should be used in pregnant women only if the potential benefits justify the potential risk to the fetus. There are no adequate and well-controlled studies of naloxegol in pregnant women. Because of the immature fetal blood-brain barrier, use of naloxegol during pregnancy may precipitate opiate withdrawal in the fetus. No adverse effects of the drug on embryofetal development have been observed in animal reproduction studies.

It is not known whether naloxegol is distributed into human milk; however, naloxegol is distributed into milk in rats and is absorbed in nursing rat pups. Because of the potential for serious adverse effects, including opiate withdrawal, in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

In clinical studies of naloxegol, 11% of patients were 65 years of age and older, while 2% were 75 years of age and older. Although no overall differences in efficacy or safety were observed between geriatric patients and younger adults, and other clinical experience revealed no evidence of age-related differences in response, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Naloxegol exposure was higher in healthy geriatric Japanese individuals compared with younger individuals; however, no dosage adjustment is required in geriatric patients.