Naloxegol is an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain. Naloxegol has been shown to be efficacious in patients who have taken opioids for at least 4 weeks. At recommended doses, naloxegol functions peripherally in GI tissues with limited CNS penetration. It is metabolized via CYP3A isoenzymes and dose adjustments are recommended in patients taking CYP3A4 inhibitors/inducers. The most common adverse reactions reported in clinical trials were abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache. Naloxegol was approved by the FDA September 2014.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Discontinue all maintenance laxative therapy prior to initiation of naloxegol. Laxative(s) can be used as needed if there is a suboptimal response to therapy after 3 days.
-Administer on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal.
-Avoid coadministration of grapefruit or grapefruit juice during treatment with naloxegol.
-Discontinue naloxegol therapy if treatment with the opioid pain medication is also discontinued.
Oral Solid Formulations
-Swallow tablet whole. Do not cut or chew.
Extemporaneous Compounding-Oral
-For patients unable to swallow the tablet whole: The tablet may be crush into a powder and mixed with 4 fluid ounces (120 mL) of water; the mixture must be drunk immediately. Refill the glass with an addition 4 fluid ounces of water, stir, and drink.
-For nasogastric (NG) tube administration: Flush the NG tube with 1 fluid ounce (30 mL) of water using a 60 mL syringe. Crush the tablet into powder, and mix with approximately 2 fluid ounces (60 mL) of water. Draw up the mixture into a 60 mL syringe and administer syringe contents into NG tube. Add another 2 fluid ounces of water to the same container used to prepare the dose. Draw up the water using the same syringe and use all the water to flush the NG tube.
Postmarketing cases of GI perforation, including fatal cases, were reported when naloxegol was used in patients at risk of GI perforation (e.g., infiltrative GI tract malignancy, recent GI tract surgery, diverticular disease including diverticulitis, ischemic colitis, or concomitantly treated with bevacizumab). Consider the risk-benefit profile when using naloxegol in this population. Monitor for the development of severe, persistent or worsening abdominal pain; discontinue treatment in patients who develop this symptom. In clinical studies of naloxegol, overall safety data for a total of 1497 naloxegol treated patients, including 537 patients treated for greater than 6 months and 320 patients treated for 12 months were reported. GI related adverse reactions for patients receiving 25 mg or 12.5 mg naloxegol were reported relative to placebo: abdominal pain (21%, 12%, vs. 7%), diarrhea (9%, 6%, vs. 5%), nausea (8%, 7%, vs. 5%), flatulence (6%, 3%, vs. 3%), and vomiting (5%, 3%, vs. 4%). In addition, possible opioid withdrawal has occurred in patients receiving naloxegol. Signs of opiate withdrawal may include GI symptoms such as diarrhea and abdominal pain. Of note, patients receiving methadone as therapy for their pain condition were observed to have a higher frequency of GI adverse reactions compared to patients receiving other opioids.
Monitor for symptoms of opioid withdrawal in patients receiving naloxegol. Possible opioid withdrawal, defined as at least 3 adverse reactions potentially related to opioid withdrawal that occurred on the same day and were not all related to the GI system, occurred in 3% and 1% of patients treated with 25 mg or 12.5 mg naloxegol, respectively. Symptoms included but were not limited to hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. In clinical studies of naloxegol, overall safety data for a total of 1,497 naloxegol treated patients, including 537 patients treated for greater than 6 months and 320 patients treated for 12 months were reported. Adverse reactions for patients receiving 25 mg or 12.5 mg naloxegol, respectively: headache (4%) and hyperhidrosis (3%, less than 1%).
Hypersensitivity reactions, including angioedema, rash, and urticaria have been reported during postmarketing experience with naloxegol.
Limited available data with naloxegol use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. There are no well-controlled studies in pregnant women. The use of naloxegol during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal studies, no effects on embryo-fetal development were observed following administration of naloxegol in pregnant rats or rabbits during the period of organogenesis at doses up to 1452 and 409 times (respectively) the human AUC at the maximum recommended human dose. According to the manufacturer, naloxegol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether naloxegol is present in human milk; however, naloxegol is present in rat milk and is absorbed in nursing rat pups. Because of the potential for serious adverse reactions, including opioid withdrawal in breast-feeding infants, the manufacturer recommends that a decision be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Naloxegol is contraindicated in patients with known or suspected GI obstruction and in patients at increased risk of recurrent obstruction, due to the potential for GI perforation. Postmarketing cases of GI perforation, including fatal cases, were reported when naloxegol was used in patients at risk of GI perforation (e.g., infiltrative GI tract malignancy, recent GI tract surgery, diverticular disease including diverticulitis, ischemic colitis, or concomitantly treated with bevacizumab). Patients with current symptoms (e.g., severe, persistent or worsening abdominal pain) that may be suggestive of GI obstruction should be evaluated before using naloxegol. Common causes of obstruction include abdominal adhesions, hernias, tumors (gastric cancer, disseminated intraperitoneal cancer), foreign bodies (including gallstones, cholelithiasis), diverticulitis, inflammatory bowel disease (Crohn's disease), and fecal impaction. Take into account the overall risk-benefit profile when using naloxegol in patients with these conditions. Monitor for the development of severe, persistent or worsening abdominal pain and/or diarrhea. In some reports, drug-associated abdominal pain and diarrhea have been severe enough to require hospitalization; most of these cases occurred within a few days of initiating treatment with the 25 mg dose. Discontinue therapy if such symptoms were to occur. If appropriate, consideration may be given to restarting therapy at 12.5 mg once daily.
In clinical evaluation, some subjects with CrCl < 60 mL/min (i.e., moderate, severe or end-stage renal failure) were shown to exhibit markedly higher systemic exposure of naloxegol compared to subjects with normal renal function. The reason for these high exposures is not understood. However, as the risk of adverse reactions increases with systemic exposure, a lower starting dosage of naloxegol is recommended in patients with marked renal disease. No dosage adjustment is needed in patients with mild renal impairment.
Avoid use of naloxegol in patients with severe hepatic disease (Child-Pugh Class C) since the pharmacokinetics of naloxegol has not been evaluated and dosage in these patients has not been determined. No dosage adjustment is required for patients with mild or moderate hepatic impairment.
Naloxegol is an antagonist of opioid binding at the mu-opioid receptor. When administered at recommended doses, naloxegol functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract; CNS penetration of naloxegol is expected to be negligible. Nevertheless, symptoms consistent with acute opioid withdrawal (e.g., hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning) have occurred in patients treated with naloxegol. In addition, compared to patients receiving other opioids, patients receiving methadone were observed in clinical trials to have a higher frequency of gastrointestinal adverse reactions that may have been related to opioid withdrawal. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Take into account the overall risk-benefit profile when using naloxegol in such patients; monitor for symptoms of opioid withdrawal.
For the treatment of opiate agonist-induced constipation in patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation:
Oral dosage:
Adults: 25 mg PO once daily, taken on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal. Reduce dose to 12.5 mg PO once daily if patient is unable to tolerate full dose. Discontinue all maintenance laxative therapy prior to initiation of naloxegol; laxative(s) can be used as needed if there is a suboptimal response to therapy after 3 days. Alteration in analgesic dosing regimen prior to initiating naloxegol is not required. Discontinue naloxegol if the opioid pain medication is discontinued.
Maximum Dosage Limits:
-Adults
25 mg PO daily.
-Geriatric
25 mg PO daily.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Avoid use of naloxegol in patients with severe hepatic impairment, as the dosage in these patients has not been determined. No dosage adjustment is required for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol has not been evaluated.
Patients with Renal Impairment Dosing
For patients with CrCl less than 60 mL/minute (i.e., moderate, severe, or end-stage renal disease), initiate dose at 12.5 mg PO once daily. If dose is tolerated, however symptoms persist, the dose may be increased to 25 mg PO once daily. Monitor closely for adverse reactions.
*non-FDA-approved indication
Adagrasib: (Contraindicated) Concomitant use of naloxegol with adagrasib is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A inhibitors, such as adagrasib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Alvimopan: (Major) Avoid coadministration of alvimopan and other opiate antagonists, like naloxegol. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Concomitant use of naloxegol with strong CYP3A4 inhibitors is contraindicated. Naloxegol is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inhibitors, such as clarithromycin, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Apalutamide: (Major) Coadministration of naloxegol with apalutamide is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Aprepitant, Fosaprepitant: (Major) Avoid concomitant administration of naloxegol and aprepitant, fosaprepitant due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Atazanavir: (Contraindicated) Concomitant use of naloxegol with atazanavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as atazanavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Atazanavir; Cobicistat: (Contraindicated) Concomitant use of naloxegol with atazanavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as atazanavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. (Contraindicated) Concomitant use of naloxegol with cobicistat is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as cobicistat, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Berotralstat: (Major) Avoid concomitant administration of naloxegol and berotralstat due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Buprenorphine; Naloxone: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Bupropion; Naltrexone: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Carbamazepine: (Major) Coadministration of naloxegol with carbamazepine is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Ceritinib: (Contraindicated) Concomitant use of naloxegol with ceritinib is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ceritinib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Chloramphenicol: (Contraindicated) Concomitant use of naloxegol with chloramphenicol is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as chloramphenicol, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Cimetidine: (Minor) Although naloxegol is metabolized primarily by the CYP3A enzyme system, concomitant use with weak CYP3A4 inhibitors, such as cimetidine, is not expected to effect naloxegol concentrations in a clinically significant manner. No dosage adjustments are necessary.
Ciprofloxacin: (Major) Avoid concomitant administration of naloxegol and ciprofloxacin due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Clarithromycin: (Contraindicated) Concomitant use of naloxegol with strong CYP3A4 inhibitors is contraindicated. Naloxegol is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inhibitors, such as clarithromycin, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Cobicistat: (Contraindicated) Concomitant use of naloxegol with cobicistat is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as cobicistat, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Conivaptan: (Major) Avoid concomitant administration of naloxegol and conivaptan due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased naloxegol exposure by approximately 3.4-fold.
Crizotinib: (Major) Avoid concomitant administration of naloxegol and crizotinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Cyclosporine: (Major) Avoid concomitant administration of naloxegol and cyclosporine due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Dabrafenib: (Major) The concomitant use of dabrafenib and naloxegol may lead to decreased naloxegol concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of naloxegol efficacy. Dabrafenib is a moderate CYP3A4 inducer and naloxegol is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
Danazol: (Major) Avoid concomitant administration of naloxegol and danazol due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Darunavir: (Contraindicated) Concomitant use of naloxegol with darunavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as darunavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Darunavir; Cobicistat: (Contraindicated) Concomitant use of naloxegol with cobicistat is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as cobicistat, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. (Contraindicated) Concomitant use of naloxegol with darunavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as darunavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Concomitant use of naloxegol with cobicistat is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as cobicistat, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. (Contraindicated) Concomitant use of naloxegol with darunavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as darunavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Delavirdine: (Contraindicated) Concomitant use of naloxegol with delavirdine is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as delavirdine, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Diltiazem: (Major) Avoid concomitant administration of naloxegol and diltiazem due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with diltiazem increased naloxegol exposure by approximately 3.4-fold.
Dronedarone: (Major) Avoid concomitant administration of naloxegol and dronedarone due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Duvelisib: (Major) Avoid concomitant administration of naloxegol and duvelisib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Concomitant use of naloxegol with cobicistat is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as cobicistat, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concomitant use of naloxegol with cobicistat is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as cobicistat, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Encorafenib: (Major) Coadministration of naloxegol with encorafenib is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration of another strong CYP3A inducer decreased naloxegol exposure by 89%.
Enzalutamide: (Major) Coadministration of naloxegol with enzalutamide is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Erythromycin: (Major) Avoid concomitant administration of naloxegol and erythromycin due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Fedratinib: (Major) Avoid concomitant administration of naloxegol and fedratinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Fluconazole: (Major) Avoid concomitant administration of naloxegol and fluconazole due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Fluvoxamine: (Major) Avoid concomitant administration of naloxegol and fluvoxamine due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Fosamprenavir: (Major) Avoid concomitant administration of naloxegol and fosamprenavir due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A substrate; fosamprenavir is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased naloxegol exposure by approximately 3.4-fold.
Fosphenytoin: (Major) Coadministration of naloxegol with fosphenytoin is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Grapefruit juice: (Contraindicated) Patients should avoid grapefruit and grapefruit juice during naloxegol treatment. Concomitant use of naloxegol with grapefruit juice is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as grapefruit juice, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Idelalisib: (Contraindicated) Concomitant use of naloxegol with idelalisib is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as idelalisib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Imatinib: (Major) Avoid concomitant administration of naloxegol and imatinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Indinavir: (Contraindicated) Concomitant use of naloxegol with indinavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as indinavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Isavuconazonium: (Major) Avoid concomitant administration of naloxegol and isavuconazonium due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; isavuconazonium is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of naloxegol with rifampin is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased naloxegol exposure by 89%.
Isoniazid, INH; Rifampin: (Major) Coadministration of naloxegol with rifampin is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased naloxegol exposure by 89%.
Itraconazole: (Contraindicated) Concomitant use of naloxegol with itraconazole is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as itraconazole, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Ivosidenib: (Moderate) Monitor for loss of efficacy of naloxegol during coadministration of ivosidenib; a naloxegol dose adjustment may be necessary. Naloxegol is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased naloxegol concentrations.
Ketoconazole: (Contraindicated) Concomitant use of naloxegol with ketoconazole is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ketoconazole, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Concomitant use of naloxegol with strong CYP3A4 inhibitors is contraindicated. Naloxegol is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inhibitors, such as clarithromycin, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Lefamulin: (Major) Avoid concomitant administration of naloxegol and oral lefamulin due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Lenacapavir: (Major) Avoid concomitant administration of naloxegol and lenacapavir due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A substrate; lenacapavir is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased naloxegol exposure by approximately 3.4-fold.
Letermovir: (Major) Avoid concomitant administration of naloxegol and letermovir due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Concurrent use is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Naloxegol is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold. Coadministration of a strong CYP3A4 inhibitor increased naloxegol exposure by more than 12-fold.
Levoketoconazole: (Contraindicated) Concomitant use of naloxegol with ketoconazole is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ketoconazole, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Lonafarnib: (Contraindicated) Concomitant use of naloxegol with lonafarnib is contraindicated. Naloxegol is metabolized primarily by CYP3A4. Strong CYP3A4 inhibitors, such as lonafarnib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Lopinavir; Ritonavir: (Contraindicated) Concomitant use of naloxegol with ritonavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ritonavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Lumacaftor; Ivacaftor: (Major) Coadministration of naloxegol with lumacaftor; ivacaftor is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Lumacaftor; Ivacaftor: (Major) Coadministration of naloxegol with lumacaftor; ivacaftor is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Methylnaltrexone: (Major) Avoid coadministration of methylnaltrexone and other opiate antagonists, like naloxegol. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
Mifepristone: (Contraindicated) Concomitant use of naloxegol with chronic mifepristone therapy is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as mifepristone, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. The clinical significance of this interaction when mifepristone is used for pregnancy termination is not established.
Mitotane: (Major) Coadministration of naloxegol with mitotane is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Naldemedine: (Major) Avoid concomitant use of naldemedine and naloxegol because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Nalmefene: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Naloxone: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Naltrexone: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Nefazodone: (Contraindicated) Concomitant use of naloxegol with nefazodone is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as nefazodone, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nelfinavir: (Contraindicated) Concomitant use of naloxegol with nelfinavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as nelfinavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid concomitant administration of naloxegol and netupitant due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nilotinib: (Major) Avoid concomitant administration of naloxegol and nilotinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nirmatrelvir; Ritonavir: (Contraindicated) Concomitant use of naloxegol with ritonavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ritonavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and naloxegol is contraindicated due to the potential for opioid withdrawal symptoms; consider an alternative COVID-19 therapy. Coadministration can significantly increase naloxegol exposure which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate and nirmatrelvir is a CYP3A inhibitor.
Nirogacestat: (Major) Avoid concomitant administration of naloxegol and nirogacestat due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased naloxegol exposure by approximately 3.4-fold.
Olanzapine; Samidorphan: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Pentazocine; Naloxone: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Phenobarbital: (Major) Coadministration of naloxegol with phenobarbital is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of naloxegol with phenobarbital is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Phenytoin: (Major) Coadministration of naloxegol with phenytoin is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Posaconazole: (Contraindicated) Concomitant use of naloxegol with posaconazole is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as posaconazole, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Primidone: (Major) Coadministration of naloxegol with primidone is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; phenobarbital, the active metabolite of primidone, is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Quinine: (Major) Avoid concomitant administration of naloxegol and quinine due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; quinine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Ribociclib: (Contraindicated) Concomitant use of naloxegol with ribociclib is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A inhibitors, such as ribociclib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Ribociclib; Letrozole: (Contraindicated) Concomitant use of naloxegol with ribociclib is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A inhibitors, such as ribociclib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Rifampin: (Major) Coadministration of naloxegol with rifampin is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased naloxegol exposure by 89%.
Rifapentine: (Major) Coadministration of naloxegol with rifapentine is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Ritlecitinib: (Major) Avoid concomitant administration of naloxegol and ritlecitinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A substrate; ritlecitinib is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased naloxegol exposure by approximately 3.4-fold.
Ritonavir: (Contraindicated) Concomitant use of naloxegol with ritonavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ritonavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Saquinavir: (Contraindicated) Concomitant use of naloxegol with saquinavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as saquinavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
St. John's Wort, Hypericum perforatum: (Major) Coadministration of naloxegol with St. John's Wort is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Stiripentol: (Moderate) Consider a dose adjustment of naloxegol when coadministered with stiripentol. Coadministration may alter plasma concentrations of naloxegol resulting in an increased risk of adverse reactions and/or decreased efficacy. Naloxegol is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Tipranavir: (Contraindicated) Concomitant use of naloxegol with tipranavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as tipranavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Trandolapril; Verapamil: (Major) Avoid concomitant administration of naloxegol and verapamil due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Tucatinib: (Contraindicated) Concomitant use of naloxegol with tucatinib is contraindicated. Naloxegol is metabolized primarily by CYP3A4. Strong CYP3A4 inhibitors, such as tucatinib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Verapamil: (Major) Avoid concomitant administration of naloxegol and verapamil due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Contraindicated) Concomitant use of naloxegol with strong CYP3A4 inhibitors is contraindicated. Naloxegol is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inhibitors, such as clarithromycin, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Voriconazole: (Contraindicated) Concomitant use of naloxegol with voriconazole is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as voriconazole, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Voxelotor: (Major) Avoid concomitant administration of naloxegol and voxelotor due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A substrate; voxelotor is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased naloxegol exposure by approximately 3.4-fold.
Naloxegol is an antagonist of opioid binding at the mu-opioid receptor and a PEGylated derivative of naloxone. Naloxegol is also a substrate of the P-glycoprotein transporter (P-gp). Its P-gp substrate properties, which increase efflux across the blood-brain barrier, coupled with the presence of the PEG moiety, reduce the CNS penetration of naloxegol compared to naloxone. When administered at the recommended dose levels, naloxegol functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids. The potential for interference with centrally mediated opioid analgesia is limited with naloxegol use at recommended doses.
Naloxegol is administered orally. Plasma protein binding of naloxegol in humans is low (approximately 4.2%). In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine and feces. Naloxegol metabolism occurs via the cytochrome P450 isoenzyme system. Metabolites are formed via N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain. Human metabolism data suggests absence of major metabolites. The activity of the metabolites at the opioid receptor has not been determined. Following oral administration of radio-labelled naloxegol, 68% and 16% of total administered dose were recovered in the feces and urine, respectively. Parent naloxegol excreted in the urine accounted for less than 6% of the total administered dose. Approximately 16% of radioactivity in feces was noted to be unchanged naloxegol, while the remaining was attributed to metabolites. Thus, renal excretion is a minor clearance pathway for naloxegol. In a clinical pharmacology study, the half-life of naloxegol at therapeutic doses ranged from 6 to 11 hours.
Affected cytochrome P450 isoenzymes: CYP3A
Naloxegol is metabolized primarily by the CYP3A enzyme system.
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, naloxegol is absorbed with peak concentrations (Cmax) achieved at less than 2 hours. In a majority of patients, a secondary Cmax is observed approximately 0.4 to 3 hours after the first peak. Across the range of doses evaluated, peak plasma concentration and area under the plasma concentration-time curve (AUC) increase in a dose-proportional or almost dose-proportional manner; accumulation is minimal following multiple daily doses. Naloxegol tablets may be swallowed whole or crush, mixed with water, and administered orally or via nasogastric tube. Systemic drug concentrations achieved following administration of the crush tablets are comparable to those observed with the whole tablets. A high-fat meal increase the extent and rate of naloxegol absorption. The Cmax and AUC are increased by approximately 30% and 45%, respectively. In clinical trials, the drug was dosed on an empty stomach approximately 1 hour prior to the first meal in the morning.
-Special Populations
Hepatic Impairment
In pharmacokinetic analysis of naloxegol, slight decreases in the AUC of naloxegol were observed in subjects with mild and moderate hepatic impairment (Child-Pugh Classes A and B, n = 8 per group) compared to subjects with normal hepatic function (n = 8), following administration of a single 25 mg oral dose of naloxegol. No dosage adjustment is required for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol has not been evaluated; avoid use of naloxegol in patients with severe hepatic impairment.
Renal Impairment
In pharmacokinetic analysis of naloxegol, the effect of renal impairment on a 25 mg single oral dose of naloxegol was studied in subjects with renal impairment (moderate, n = 8; severe, n = 4; end-stage renal disease not yet on dialysis, n = 4) compared with healthy subjects. Most renal impairment subjects had plasma naloxegol pharmacokinetics comparable to those in healthy subjects. However, several individuals with renal impairment demonstrated higher naloxegol exposures (up to 10- fold) compared to the controls. The reason for these high exposures is unknown. This study also included 8 end-stage renal disease patients on hemodialysis. Plasma concentrations of naloxegol in these subjects were similar to healthy volunteers with normal renal function, when naloxegol was administered either pre- or post-hemodialysis. Therefore, for patients with CrCl < 60 mL/min (i.e., moderate, severe, or end-stage renal disease), dosing adjustments are recommended along with increased monitoring for adverse reactions.
Geriatric
In pharmacokinetic analysis of naloxegol, the mean steady-state Cmax and AUC values seen in elderly healthy Japanese subjects (n = 6) were approximately 45% and 54% greater than those obtained in young healthy subjects (n = 6) following multiple daily doses of naloxegol (25 mg). No guidance are available regarding dosing adjustments based on age differences.
Gender Differences
There is no gender effect on the pharmacokinetics of naloxegol.
Ethnic Differences
A pharmacokinetic analysis of naloxegol found systemic drug exposures and peak drug concentrations to be 20% and 10%, respectively, lower in Black patients than in Caucasians; however, Asian patients reach peak concentrations that are 30% higher than Caucasians.