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Uses

Opiate-induced Constipation

Naloxegol oxalate is used for the management of opiate-induced constipation in patients with chronic non-cancer-related pain.

Safety and efficacy of naloxegol were established in 2 identical randomized, double-blind, placebo-controlled, phase 3 studies (KODIAC-04 and KODIAC-05) in 1352 patients (mean age of 52 years) with non-cancer-related pain and active opiate-induced constipation who had received an oral opiate analgesic (at a stable dosage equivalent to 30 mg to 1 g of morphine sulfate daily) for at least 4 weeks prior to study enrollment. Opiate-induced constipation was defined as fewer than 3 spontaneous bowel movements per week during the 4 weeks prior to screening, with at least 25% of spontaneous bowel movements associated with straining, hard or lumpy stools, and/or a sensation of incomplete evacuation or anorectal obstruction. Patients with suspected clinically important disruptions of the blood-brain barrier were not enrolled in the studies. Patients in the studies were randomized to receive naloxegol 12.5 or 25 mg once daily or placebo for 12 weeks. No laxatives or bowel-therapy regimens other than a ''rescue'' laxative regimen (up to three 10- to 15-mg doses of bisacodyl followed, if necessary, by one-time use of an enema for an episode of no bowel movements for 72 hours) were permitted during the studies. Back pain (56-57%) and arthritis (10%) were the most common indications for opiate analgesia in the 2 studies. Patients enrolled in the studies had received their current opiate analgesic for an average of 3.6-3.7 years. The mean baseline opiate dosage was equivalent to 136-140 mg of morphine sulfate daily.

Laxative use on at least one occasion within 2 weeks prior to study enrollment was reported by 71% of patients. Approximately 53-55% of patients enrolled in the studies had an inadequate response to laxatives prior to study enrollment. Inadequate response to laxatives was defined as laxative use on at least 4 of the previous 14 days with at least 1 of the following symptoms of moderate, severe, or very severe intensity: incomplete bowel movements, hard stool, straining, or sensation of needing to pass a bowel movement but being unable to do so. In the subgroup of patients with inadequate response to laxatives, 42-50% of patients reported daily use of laxatives, most frequently stool softeners (18-24%), stimulants (16-18%), and polyethylene glycol (5-6%), prior to enrollment. Combined use of 2 laxative classes was reported by 27-31% of these patients at any time during the 14 days prior to enrollment; the most commonly reported combination was stimulants and stool softeners (8-10%).

The primary end point of the studies was response, defined as 3 or more spontaneous bowel movements per week and a change from baseline of 1 or more spontaneous bowel movements per week for at least 9 of the 12 study weeks and at least 3 of the final 4 study weeks. Response to naloxegol 25 mg daily was superior to the placebo response in both studies; however, response to naloxegol 12.5 mg daily was superior to the placebo response in only one of the studies. Response rates for naloxegol 25 mg, naloxegol 12.5 mg, and placebo were 44, 41, and 29%, respectively, in KODIAC-04 and 40, 35, and 29%, respectively, in KODIAC-05.

Key secondary end points of the studies included time to first postdose spontaneous bowel movement, change from baseline in the mean number of days per week with 1-3 spontaneous bowel movements, and response rate in patients with an inadequate response to laxatives prior to study enrollment. On each of these 3 key secondary end points, naloxegol 25 mg daily was superior to placebo in both studies and naloxegol 12.5 mg daily was superior to placebo in KODIAC-04; statistical significance for secondary end points could not be established for the 12.5-mg dosage in KODIAC-05 since this study failed to established efficacy of the 12.5-mg dosage for the primary efficacy end point. In the subgroup of patients with an inadequate response to laxatives, response rates were 49, 43, and 29% in KODIAC-04 for naloxegol 25 mg, naloxegol 12.5 mg, and placebo, respectively, and 47 and 31% in KODIAC-05 for naloxegol 25 mg and placebo, respectively. In KODIAC-04, median times to first postdose spontaneous bowel movement were 6, 20, and 36 hours with naloxegol 25 mg, naloxegol 12.5 mg, and placebo, respectively. In KODIAC-05, median times to first postdose spontaneous bowel movement were 12 and 37 hours with naloxegol 25 mg and placebo, respectively. A spontaneous bowel movement occurred within 24 hours of the first dose in 61-70 or 58% of patients receiving naloxegol 25 or 12.5 mg, respectively.

Mean daily opiate dosages remained stable during the studies, and mean changes from baseline in pain intensity (as measured on a scale of 0-10) were small and not clinically important.

Dosage and Administration

General

All maintenance laxative therapy should be discontinued prior to initiating naloxegol; laxatives may be used as needed if the patient's response to naloxegol is suboptimal after 3 days of therapy.

Changes in the analgesic dosing regimen are not required prior to initiation of naloxegol therapy. Naloxegol has been shown to be efficacious in patients who have taken opiates for at least 4 weeks. Sustained exposure to opiates prior to initiation of naloxegol may increase sensitivity to the effects of the drug. Naloxegol should be discontinued if therapy with opiate analgesics is discontinued.

Administration

Naloxegol oxalate is administered orally on an empty stomach at least 1 hour before or 2 hours after the first meal of the day. Naloxegol oxalate tablets should be swallowed intact and should not be crushed or chewed.

Dosage

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.)

Special Populations

The recommended initial dosage of naloxegol in patients with moderate or severe renal impairment (i.e., creatinine clearance less than 60 mL/minute), including those with end-stage renal disease, is 12.5 mg once daily. If the initial naloxegol dosage is well tolerated but symptoms of opiate-induced constipation persist, dosage may be increased to 25 mg once daily, taking into consideration the potential for markedly increased systemic exposure to the drug in some patients with renal impairment and the associated increased risk of adverse effects.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is needed in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Use of naloxegol should be avoided in patients with severe (Child-Pugh class C) hepatic impairment; an appropriate dosage has not been established.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is required in geriatric patients based solely on age.

Cautions

Contraindications

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.

Warnings/Precautions

GI Perforation

GI perforation has been reported with use of methylnaltrexone, another peripherally acting opiate antagonist, in patients with underlying conditions that may be associated with localized or diffuse reduction of structural integrity in the GI tract wall (e.g., peptic ulcer disease, Ogilvie's syndrome, diverticular disease, infiltrative GI tract malignancies or peritoneal metastases). Risks and benefits of naloxegol therapy should be carefully considered in patients with these conditions or with other conditions that might result in impaired integrity of the GI tract wall (e.g., Crohn's disease). Patients receiving naloxegol should be monitored for the development of severe, persistent, or worsening abdominal pain. Naloxegol should be discontinued if such symptoms occur.

Opiate Withdrawal

In 2 controlled clinical trials of naloxegol in patients with opiate-induced constipation, possible opiate withdrawal (defined as the same-day occurrence of at least 3 adverse effects, not all related to the GI tract, that are potential manifestations of opiate withdrawal [e.g., hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, yawning]) occurred in 1% of patients receiving naloxegol 12.5 mg daily, 3% of patients receiving naloxegol 25 mg daily, and less than 1% of those receiving placebo. In both trials, the incidence of adverse GI effects potentially related to opiate withdrawal was higher in patients receiving methadone compared with those receiving other opiate analgesics (39 versus 26% of those receiving naloxegol 12.5 mg daily and 75 versus 34% of those receiving naloxegol 25 mg daily). Patients with disruptions in the blood-brain barrier may be at increased risk for opiate withdrawal or reduced analgesia; risks and benefits of naloxegol therapy should be carefully considered in such patients, and these patients should be monitored for symptoms of opiate withdrawal.

Specific Populations

Pregnancy

Category C.

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.

Lactation

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.

Pediatric Use

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

Geriatric Use

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.

Hepatic Impairment

Following oral administration of a single 25-mg dose of naloxegol, slight decreases in area under the concentration-time curve (AUC) of the drug were observed in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment compared with those with normal hepatic function. No dosage adjustment is required in 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 established. Use of naloxegol in patients with severe hepatic impairment should be avoided, as appropriate dosage in these patients has not been determined.

Renal Impairment

Following oral administration of a single 25-mg dose of naloxegol in patients with moderate or severe renal impairment or end-stage renal disease not yet requiring dialysis (i.e., creatinine clearance less than 60 mL/minute), the pharmacokinetic profile of naloxegol in most patients was similar to that observed in healthy individuals. However, some patients with renal impairment (including patients with moderate, severe, or end-stage renal disease) had markedly increased systemic exposure to the drug (e.g., up to tenfold higher than that observed in healthy individuals). Some patients with end-stage renal disease requiring dialysis also were included in the pharmacokinetic study. Plasma concentrations of naloxegol in these patients were similar to concentrations observed in healthy individuals whether the drug was administered before or after hemodialysis.

The reason for the high exposures observed in some patients with renal impairment is unknown; however, because the risk of adverse effects increases as systemic exposure increases, a reduced initial dosage of naloxegol is recommended in patients with creatinine clearances of less than 60 mL/minute.(See Dosage and Administration: Special Populations.) No dosage adjustment is required in patients with mild renal impairment.

Common Adverse Effects

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.

Drug Interactions

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.

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of naloxegol with potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole) or moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) may result in increased plasma concentrations of naloxegol and increased risk of adverse effects. Use of naloxegol with potent CYP3A4 inhibitors is contraindicated. Use of naloxegol with moderate CYP3A4 inhibitors should be avoided; if concomitant use is unavoidable, dosage of naloxegol should be reduced to 12.5 mg once daily and the patient should be monitored for adverse effects. When naloxegol is used concomitantly with weak CYP3A4 inhibitors (e.g., cimetidine, quinidine), clinically important increases in naloxegol concentrations are not expected and dosage adjustments are not required.

Potent CYP3A4 inducers (e.g., carbamazepine, rifampin, St. John's wort [Hypericum perforatum]) can substantially decrease plasma naloxegol concentrations and may decrease the efficacy of naloxegol. Use of naloxegol with potent CYP3A4 inducers is not recommended.

Diltiazem

Concomitant administration of naloxegol (single 25-mg dose) and the combined P-gp and moderate CYP3A4 inhibitor diltiazem (240 mg of extended-release diltiazem hydrochloride once daily) increased peak plasma concentration and area under the concentration-time curve (AUC) of naloxegol by 2.9- and 3.4-fold, respectively. Concomitant use of naloxegol with diltiazem should be avoided; if concomitant use cannot be avoided, dosage of naloxegol should be reduced to 12.5 mg once daily and the patient should be monitored for adverse effects.

Efavirenz

Pharmacokinetic simulations suggested that concomitant administration of a single 25-mg dose of naloxegol with the moderate CYP3A inducer efavirenz (400 mg once daily) results in naloxegol exposures similar to those achieved with administration of naloxegol 12.5 mg alone (i.e., a 50% reduction in exposure).

Grapefruit or Grapefruit Juice

When consumed concomitantly with naloxegol, grapefruit or grapefruit juice can increase plasma naloxegol concentrations. Consumption of grapefruit or grapefruit juice should be avoided by patients receiving naloxegol. The manufacturer states that the effect of grapefruit juice varies widely among brands and is dependent on the concentration, dose, and preparation. Studies have demonstrated that some preparations of grapefruit juice (e.g., high dose, double strength) are potent CYP3A inhibitors, while other preparations (e.g., low dose, single strength) are moderate CYP3A inhibitors.

Ketoconazole

Concomitant administration of naloxegol (single 25-mg dose) and the combined P-gp and potent CYP3A4 inhibitor ketoconazole (400 mg once daily) increased peak plasma concentration and AUC of naloxegol by 9.6- and 12.9-fold, respectively. Concomitant use of naloxegol with ketoconazole is contraindicated.

Morphine

In healthy individuals receiving IV morphine sulfate (5 mg per 70 kg), single doses of naloxegol (8 mg to 1 g) had no meaningful effect on systemic exposure to morphine or its major circulating metabolites. With increasing naloxegol dose, there was no trend toward increasing or decreasing morphine exposure compared with morphine administered alone.

Opiate Antagonists

When naloxegol is used concomitantly with other opiate antagonists, the potential exists for additive opiate receptor antagonism and an increased risk of opiate withdrawal. Concomitant use of naloxegol with other opiate antagonists should be avoided.

Quinidine

Because of its inhibitory effect on P-gp, the combined potent P-gp and weak CPY3A4 inhibitor quinidine sulfate (single 600-mg dose) increased peak plasma concentration and AUC of naloxegol (given as a single 25-mg dose) by 2.5- and 1.4-fold, respectively. However, no dosage adjustment is necessary.

Rifampin

Concomitant administration of naloxegol (single 25-mg dose) and the combined P-gp and potent CYP3A4 inducer rifampin (600 mg once daily) decreased peak plasma concentration and AUC of naloxegol by 76 and 89%, respectively. Concomitant use of naloxegol with rifampin is not recommended.

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