naloxegol 25 MG Oral Tablet [Movantik]

INDICATIONS AND USAGE MOVANTIK ® is indicated for the treatment of opioid-induced constipation (OIC) in adult 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. MOVANTIK is an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult 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. (1)

DOSAGE AND ADMINISTRATION Administration : Discontinue maintenance laxative therapy before starting MOVANTIK; may resume laxatives if patients have OIC symptoms after taking MOVANTIK for 3 days. (2.1) Alteration in analgesic dosing regimen prior to starting MOVANTIK is not required. (2.1) Patients receiving opioids for less than 4 weeks may be less responsive to MOVANTIK. (2.1) Take on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal. (2.1) For patients who are unable to swallow the MOVANTIK tablet whole, the tablet can be crushed and given orally or administered via nasogastric tube, see full prescribing information. (2.1) Avoid consumption of grapefruit or grapefruit juice. (2.1 , 7.1) Discontinue if treatment with the opioid pain medication is also discontinued. (2.1) Recommended dosage : 25 mg once daily; if not tolerated, reduce to 12.5 mg once daily. (2.2) Renal Impairment (CLcr < 60 mL/min): 12.5 mg once daily; increase to 25 mg once daily if tolerated and monitor for adverse reactions. (2.3 , 8.6) 2.1 Administration Instructions Discontinue all maintenance laxative therapy prior to initiation of MOVANTIK. Laxative(s) can be used as needed if there is a suboptimal response to MOVANTIK after three days. Alteration in analgesic dosing regimen prior to initiating MOVANTIK is not required. Patients receiving opioids for less than 4 weeks may be less responsive to MOVANTIK [see Clinical Studies (14) ] . Take MOVANTIK on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal. For patients who are unable to swallow the MOVANTIK tablet whole, the tablet can be crushed to a powder, mixed with 4 ounces (120 mL) of water, and drunk immediately. The glass should be refilled with 4 ounces (120 mL) of water, stirred and the contents drunk. MOVANTIK can also be administered via a nasogastric (NG) tube, as follows: 1.Flush the NG tube with 1 ounce (30 mL) of water using a 60 mL syringe. 2.Crush the tablet to a powder in a container and mix with approximately 2 ounces (60 mL) of water. 3.Draw up the mixture using the 60 mL syringe and administer the syringe contents through the NG tube. 4.Add approximately 2 ounces (60 mL) of water to the same container used to prepare the dose of MOVANTIK. 5.Draw up the water using the same 60 mL syringe and use all the water to flush the NG tube and any remaining medicine from the NG tube into the stomach. Avoid consumption of grapefruit or grapefruit juice during treatment with MOVANTIK. Discontinue MOVANTIK if treatment with the opioid pain medication is also discontinued. 2.2 Adult Dosage The recommended MOVANTIK dosage is 25 mg once daily in the morning. If patients are not able to tolerate MOVANTIK, reduce the dosage to 12.5 mg once daily [see Clinical Pharmacology (12.2) ] . 2.3 Dosage in Adult Patients with Renal Impairment The starting dosage for patients with creatinine clearance (CLcr) <60 mL/min (i.e., patients with moderate, severe, or end-stage renal impairment) is 12.5 mg once daily. If this dosage is well tolerated but OIC symptoms continue, the dosage may be increased 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.4 Dosage Recommendations due to Drug Interactions Avoid concomitant use of MOVANTIK with moderate CYP3A4 inhibitor drugs (e.g., diltiazem, erythromycin, verapamil). If concurrent use is unavoidable, reduce the MOVANTIK dosage to 12.5 mg once daily and monitor for adverse reactions [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

WARNINGS AND PRECAUTIONS Opioid withdrawal : Consider the overall risk benefit in patients with disruptions to the blood-brain barrier. Monitor for symptoms of opioid withdrawal. (5.1) Severe abdominal pain and/or diarrhea : Monitor for the development of symptoms after initiating treatment with MOVANTIK and discontinue if severe symptoms develop. Consider restarting MOVANTIK at 12.5 mg once daily if appropriate. (5.2) Gastrointestinal perforation : Consider the overall risk benefit in patients with known or suspected lesions of the GI tract. Monitor for severe, persistent or worsening abdominal pain; discontinue if development of symptoms. (5.3) 5.1 Opioid Withdrawal Clusters of symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning have occurred in patients treated with MOVANTIK [see Adverse Reactions (6.1 )] . In addition, patients receiving methadone as therapy for their pain condition were observed in clinical trials to have a higher frequency of gastrointestinal adverse reactions that may have been related to opioid withdrawal than patients receiving other opioids [see Adverse Reactions (6.1) ] . 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 MOVANTIK in such patients. Monitor for symptoms of opioid withdrawal in such patients. 5.2 Severe Abdominal Pain and/or Diarrhea Reports of severe abdominal pain and/or diarrhea have been reported, some of which resulted in hospitalization. Most of the cases of severe abdominal pain were reported in patients taking the 25 mg dosage. Symptoms generally occurred within a few days of initiation of MOVANTIK. Monitor patients for the development of abdominal pain and/or diarrhea with MOVANTIK and discontinue therapy if severe symptoms occur. Consider restarting MOVANTIK at 12.5 mg once daily, if appropriate. 5.3 Gastrointestinal Perforation Cases of gastrointestinal (GI) perforation have been reported with use of peripherally acting opioid antagonists, including MOVANTIK. Postmarketing cases of GI perforation, including fatal cases, were reported when MOVANTIK was used in patients at risk of GI perforation (e.g., infiltrative gastrointestinal tract malignancy, recent gastrointestinal tract surgery, diverticular disease including diverticulitis, ischemic colitis, or concomitantly treated with bevacizumab). MOVANTIK is contraindicated in patients with known or suspected gastrointestinal obstruction or in patients at risk of recurrent obstruction [see Contraindications (4) ] . Take into account the overall risk-benefit profile when using MOVANTIK in patients with these conditions or other 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 MOVANTIK in patients who develop this symptom.

CONTRAINDICATIONS MOVANTIK is contraindicated in: Patients with known or suspected gastrointestinal obstruction and patients at risk of recurrent obstruction, due to the potential for gastrointestinal perforation [see Warnings and Precautions (5.3) ] . Patients concomitantly using strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) because these medications can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Patients who have had a known serious or severe hypersensitivity reaction to MOVANTIK or any of its excipients [see Adverse Reactions (6.2) ] . Patients with known or suspected gastrointestinal obstruction and at risk of recurrent obstruction. (4 , 5.3 ) Concomitant use with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole). (4 , 7.1) Known serious or severe hypersensitivity reaction to MOVANTIK or any of its excipients. (4)

Mechanism of Action Naloxegol is an antagonist of opioid binding at the mu-opioid receptor. 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. Naloxegol is a PEGylated derivative of naloxone and is a substrate for the P-glycoprotein transporter (P-gp). Also, the presence of the PEG moiety in naloxegol reduces its passive permeability as compared with naloxone. Due to the reduced permeability and increased efflux of naloxegol across the blood-brain barrier, related to P-gp substrate properties, the CNS penetration of naloxegol is expected to be negligible at the recommended dose levels limiting the potential for interference with centrally mediated opioid analgesia.