Naloxegol (Movantik—AstraZeneca), the first once-daily, oral, peripherally acting mu-opioid antagonist for the treatment of opioid-induced constipation in adults with chronic pain not related to cancer, has received FDA approval. Naloxegol is a PEGylated naloxone molecule, which reduces its passive permeability across the blood-brain barrier, compared with naloxone. Therefore, central nervous system penetration of naloxegol is expected to be negligible, limiting its potential to interfere with centrally mediated opioid analgesia.Approximately 40% to 90% of patients taking opioids have constipation and other gastrointestinal adverse effects. Opioid-induced constipation occurs as a result of opioid agonists binding to mu-opioid receptors located in the enteric nervous system. This leads to increased nonpropulsive contractions and inhibition of water and electrolyte secretion. Inhibition of gastric emptying and a delay of transit throughout the small and large intestines also occur.Currently, dietary modifications, lifestyle changes, and laxatives are used to treat opioid-induced constipation, but their efficacy is limited. Two agents have been FDA approved in recent years, methylnatrexone (Relistor—Salix) and alvimopan (Entereg—Cubist); however, both have select limitations in that alvimopan has a narrow indication and methylnatrexone must be administered via subcutaneous injection.Alvimopan is indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis. In addition, because of the potential risk of myocardial infarction with long-term use, alvimopan is available only through a restricted program for short-term use (i.e., 15 doses) under a Risk Evaluation and Mitigation Strategy. Therefore, approval of an oral agent for opioid-induced constipation without restricted access is a welcome addition for patients suffering from this condition.Patient counselingReview the Médication Guide with patients and tell them to discontinue maintenance laxatives before starting treatment. Educate them on proper administration, such as swallowing the tablets whole, taking them on an empty stomach, and avoiding consumption of grapefruit or grapefruit juice. Also inform patients of serious adverse effects (e.g., severe, persistent, or worsening abdominal pain; signs of opioid withdrawal) and more common ones (e.g., diarrhea, nausea, flatulence, vomiting, and headache).Clinical efficacy, safetyNaloxegol's approval was based on data from the KODIAC clinical program, which included two trials focused on efficacy and safety and two trials specifically dedicated to safety. The KODIAC-4 and -5 trials were 12-week, double-blind, placebo-controlled studies including 1,352 patients who had taken opioids at equivalent morphine doses of 30 mg to 1,000 mg for at least 4 weeks for pain not related to cancer and had self-reported opioid-induced constipation.The primary endpoint response was defined as three or more spontaneous bowel movements (SBMs) per week and a change from baseline of one or more SBMs per week for at least 9 out of the 12 study weeks and 3 out of the last 4 weeks. After 12 weeks of treatment, more patients given naloxegol 12.5 mg or 25 mg daily experienced a response compared with patients receiving placebo in both studies.Naloxegol (Movantik)Manufacturer: AstraZenecaDrug class: Peripherally acting muopioid antagonistIndication: Treatment of opioid-induced constipation in adults with chronic pain not related to cancerDosage: 25 mg once daily; if not tolerated, reduce to 12.5 mg once daily■Patients with renal impairment, defined as a creatinine clearance of <60 mL/min, should be initiated at a dose of 12.5 mg once daily and increased to 25 mg once daily if tolerated.■Tablets should be swallowed whole on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal.Of note: Naloxegol is contraindicated in patients with known or suspected gastrointestinal obstruction or those at increased risk of recurrent obstruction; patients on concurrent strong cytochrome (CYP)3A4 inhibitors; and those with known serious or severe hypersensitivity to the drug or any of its excipients.The KODIAC-7 trial was a 12-week extension of the KODIAC-4 trial, and the KODIAC-8 trial was a 52-week, openlabel, long-term safety study. Overall, the safety data were consistent across the four trials, with the most common adverse events reported in KODIAC-4 and -5 being abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, and hyperhidrosis.Future considerationsSince naloxegol is structurally related to noroxymorphone, it is classified as a Schedule II controlled substance. However, data indicate that naloxegol has no risk of abuse or dependency. AstraZeneca has submitted a petition to DEA requesting the descheduling of naloxegol, and the manufacturer noted that the agency will consider the request. In addition, FDA is requiring a postmarketing study that would further evaluate cardiovascular risks in patients taking naloxegol.AstraZeneca anticipates that the product will be available in the first half of 2015. Naloxegol (Movantik—AstraZeneca), the first once-daily, oral, peripherally acting mu-opioid antagonist for the treatment of opioid-induced constipation in adults with chronic pain not related to cancer, has received FDA approval. Naloxegol is a PEGylated naloxone molecule, which reduces its passive permeability across the blood-brain barrier, compared with naloxone. Therefore, central nervous system penetration of naloxegol is expected to be negligible, limiting its potential to interfere with centrally mediated opioid analgesia. Approximately 40% to 90% of patients taking opioids have constipation and other gastrointestinal adverse effects. Opioid-induced constipation occurs as a result of opioid agonists binding to mu-opioid receptors located in the enteric nervous system. This leads to increased nonpropulsive contractions and inhibition of water and electrolyte secretion. Inhibition of gastric emptying and a delay of transit throughout the small and large intestines also occur. Currently, dietary modifications, lifestyle changes, and laxatives are used to treat opioid-induced constipation, but their efficacy is limited. Two agents have been FDA approved in recent years, methylnatrexone (Relistor—Salix) and alvimopan (Entereg—Cubist); however, both have select limitations in that alvimopan has a narrow indication and methylnatrexone must be administered via subcutaneous injection. Alvimopan is indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis. In addition, because of the potential risk of myocardial infarction with long-term use, alvimopan is available only through a restricted program for short-term use (i.e., 15 doses) under a Risk Evaluation and Mitigation Strategy. Therefore, approval of an oral agent for opioid-induced constipation without restricted access is a welcome addition for patients suffering from this condition.Patient counselingReview the Médication Guide with patients and tell them to discontinue maintenance laxatives before starting treatment. Educate them on proper administration, such as swallowing the tablets whole, taking them on an empty stomach, and avoiding consumption of grapefruit or grapefruit juice. Also inform patients of serious adverse effects (e.g., severe, persistent, or worsening abdominal pain; signs of opioid withdrawal) and more common ones (e.g., diarrhea, nausea, flatulence, vomiting, and headache). Review the Médication Guide with patients and tell them to discontinue maintenance laxatives before starting treatment. Educate them on proper administration, such as swallowing the tablets whole, taking them on an empty stomach, and avoiding consumption of grapefruit or grapefruit juice. Also inform patients of serious adverse effects (e.g., severe, persistent, or worsening abdominal pain; signs of opioid withdrawal) and more common ones (e.g., diarrhea, nausea, flatulence, vomiting, and headache). Review the Médication Guide with patients and tell them to discontinue maintenance laxatives before starting treatment. Educate them on proper administration, such as swallowing the tablets whole, taking them on an empty stomach, and avoiding consumption of grapefruit or grapefruit juice. Also inform patients of serious adverse effects (e.g., severe, persistent, or worsening abdominal pain; signs of opioid withdrawal) and more common ones (e.g., diarrhea, nausea, flatulence, vomiting, and headache). Clinical efficacy, safetyNaloxegol's approval was based on data from the KODIAC clinical program, which included two trials focused on efficacy and safety and two trials specifically dedicated to safety. The KODIAC-4 and -5 trials were 12-week, double-blind, placebo-controlled studies including 1,352 patients who had taken opioids at equivalent morphine doses of 30 mg to 1,000 mg for at least 4 weeks for pain not related to cancer and had self-reported opioid-induced constipation.The primary endpoint response was defined as three or more spontaneous bowel movements (SBMs) per week and a change from baseline of one or more SBMs per week for at least 9 out of the 12 study weeks and 3 out of the last 4 weeks. After 12 weeks of treatment, more patients given naloxegol 12.5 mg or 25 mg daily experienced a response compared with patients receiving placebo in both studies.Naloxegol (Movantik)Manufacturer: AstraZenecaDrug class: Peripherally acting muopioid antagonistIndication: Treatment of opioid-induced constipation in adults with chronic pain not related to cancerDosage: 25 mg once daily; if not tolerated, reduce to 12.5 mg once daily■Patients with renal impairment, defined as a creatinine clearance of <60 mL/min, should be initiated at a dose of 12.5 mg once daily and increased to 25 mg once daily if tolerated.■Tablets should be swallowed whole on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal.Of note: Naloxegol is contraindicated in patients with known or suspected gastrointestinal obstruction or those at increased risk of recurrent obstruction; patients on concurrent strong cytochrome (CYP)3A4 inhibitors; and those with known serious or severe hypersensitivity to the drug or any of its excipients.The KODIAC-7 trial was a 12-week extension of the KODIAC-4 trial, and the KODIAC-8 trial was a 52-week, openlabel, long-term safety study. Overall, the safety data were consistent across the four trials, with the most common adverse events reported in KODIAC-4 and -5 being abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, and hyperhidrosis. Naloxegol's approval was based on data from the KODIAC clinical program, which included two trials focused on efficacy and safety and two trials specifically dedicated to safety. The KODIAC-4 and -5 trials were 12-week, double-blind, placebo-controlled studies including 1,352 patients who had taken opioids at equivalent morphine doses of 30 mg to 1,000 mg for at least 4 weeks for pain not related to cancer and had self-reported opioid-induced constipation. The primary endpoint response was defined as three or more spontaneous bowel movements (SBMs) per week and a change from baseline of one or more SBMs per week for at least 9 out of the 12 study weeks and 3 out of the last 4 weeks. After 12 weeks of treatment, more patients given naloxegol 12.5 mg or 25 mg daily experienced a response compared with patients receiving placebo in both studies.Naloxegol (Movantik)Manufacturer: AstraZenecaDrug class: Peripherally acting muopioid antagonistIndication: Treatment of opioid-induced constipation in adults with chronic pain not related to cancerDosage: 25 mg once daily; if not tolerated, reduce to 12.5 mg once daily■Patients with renal impairment, defined as a creatinine clearance of <60 mL/min, should be initiated at a dose of 12.5 mg once daily and increased to 25 mg once daily if tolerated.■Tablets should be swallowed whole on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal.Of note: Naloxegol is contraindicated in patients with known or suspected gastrointestinal obstruction or those at increased risk of recurrent obstruction; patients on concurrent strong cytochrome (CYP)3A4 inhibitors; and those with known serious or severe hypersensitivity to the drug or any of its excipients. Manufacturer: AstraZenecaDrug class: Peripherally acting muopioid antagonistIndication: Treatment of opioid-induced constipation in adults with chronic pain not related to cancerDosage: 25 mg once daily; if not tolerated, reduce to 12.5 mg once daily■Patients with renal impairment, defined as a creatinine clearance of <60 mL/min, should be initiated at a dose of 12.5 mg once daily and increased to 25 mg once daily if tolerated.■Tablets should be swallowed whole on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal.Of note: Naloxegol is contraindicated in patients with known or suspected gastrointestinal obstruction or those at increased risk of recurrent obstruction; patients on concurrent strong cytochrome (CYP)3A4 inhibitors; and those with known serious or severe hypersensitivity to the drug or any of its excipients. Manufacturer: AstraZeneca Drug class: Peripherally acting muopioid antagonist Indication: Treatment of opioid-induced constipation in adults with chronic pain not related to cancer Dosage: 25 mg once daily; if not tolerated, reduce to 12.5 mg once daily■Patients with renal impairment, defined as a creatinine clearance of <60 mL/min, should be initiated at a dose of 12.5 mg once daily and increased to 25 mg once daily if tolerated.■Tablets should be swallowed whole on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal. Of note: Naloxegol is contraindicated in patients with known or suspected gastrointestinal obstruction or those at increased risk of recurrent obstruction; patients on concurrent strong cytochrome (CYP)3A4 inhibitors; and those with known serious or severe hypersensitivity to the drug or any of its excipients. The KODIAC-7 trial was a 12-week extension of the KODIAC-4 trial, and the KODIAC-8 trial was a 52-week, openlabel, long-term safety study. Overall, the safety data were consistent across the four trials, with the most common adverse events reported in KODIAC-4 and -5 being abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, and hyperhidrosis. Future considerationsSince naloxegol is structurally related to noroxymorphone, it is classified as a Schedule II controlled substance. However, data indicate that naloxegol has no risk of abuse or dependency. AstraZeneca has submitted a petition to DEA requesting the descheduling of naloxegol, and the manufacturer noted that the agency will consider the request. In addition, FDA is requiring a postmarketing study that would further evaluate cardiovascular risks in patients taking naloxegol.AstraZeneca anticipates that the product will be available in the first half of 2015. Since naloxegol is structurally related to noroxymorphone, it is classified as a Schedule II controlled substance. However, data indicate that naloxegol has no risk of abuse or dependency. AstraZeneca has submitted a petition to DEA requesting the descheduling of naloxegol, and the manufacturer noted that the agency will consider the request. In addition, FDA is requiring a postmarketing study that would further evaluate cardiovascular risks in patients taking naloxegol. AstraZeneca anticipates that the product will be available in the first half of 2015.