Naloxegol

5 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.

6 ADVERSE REACTIONS Serious and important adverse reactions described elsewhere in labeling include: Opioid withdrawal [see Warnings and Precautions (5.1) ] Severe abdominal pain and/or diarrhea [see Warnings and Precautions (5.2) ] Gastrointestinal perforation [see Warnings and Precautions (5.3) ] The most common adverse reactions in clinical trials (≥3%) are: abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Valinor at 1-877-592-2337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to MOVANTIK in 1497 patients in clinical trials, including 537 patients exposed for greater than six months, and 320 patients exposed for 12 months. The safety data described in Table 1 are derived from two double-blind, placebo-controlled trials (Studies 1 and 2) in patients with OIC and non-cancer related pain [see Clinical Studies (14) ] . Study 3 (n=302) was a safety extension study that allowed patients from Study 1 to continue the same blinded treatment for an additional 12 weeks. Safety data for patients in Study 3 are similar to those listed in Table 1. Study 4 (n=844) was a Phase 3, 52-week, multi-center, open-label, randomized, parallel group, safety and tolerability study of naloxegol versus usual care treatment for OIC (as determined by the investigator and excluding peripheral opioid antagonists) in patients with non-cancer related pain. The population enrolled in Study 4 was similar to that of the other studies. Eligible patients were randomized in a 2:1 ratio to receive either naloxegol 25 mg once daily or usual care treatment for OIC. The most commonly used laxatives in the usual care group were rectal stimulants (e.g., bisacodyl), oral stimulants (e.g., senna), and oral osmotics (e.g., macrogol, magnesium). Safety data for patients in Study 4 are similar to those listed in Table 1. Table 1 lists adverse reactions in pooled Studies 1 and 2 occurring in ≥3% of patients receiving MOVANTIK 12.5 mg or 25 mg and at an incidence greater than placebo. Table 1. Adverse Reactions Adverse reactions occurring in ≥3% of patients receiving MOVANTIK 12.5 mg or 25 mg and at an incidence greater than placebo. in Patients with OIC and Non-Cancer Pain (Studies 1 and 2) Adverse Reaction MOVANTIK 25 mg (n=446) MOVANTIK 12.5 mg (n=441) Placebo (n=444) Abdominal Pain Includes: abdominal pain, abdominal pain upper, abdominal pain lower, and gastrointestinal pain. 21% 12% 7% Diarrhea 9% 6% 5% Nausea 8% 7% 5% Flatulence 6% 3% 3% Vomiting 5% 3% 4% Headache 4% 4% 3% Hyperhidrosis 3% <1% <1% Opioid Withdrawal Possible opioid withdrawal, defined as at least three adverse reactions potentially related to opioid withdrawal that occurred on the same day and were not all related to the gastrointestinal system, occurred in less than 1% (1/444) of placebo subjects, 1% (5/441) receiving MOVANTIK 12.5 mg, and 3% (14/446) receiving MOVANTIK 25 mg in Studies 1 and 2 regardless of maintenance opioid treatment. Symptoms included but were not limited to hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Patients receiving methadone as therapy for their pain condition were observed in Studies 1 and 2 to have a higher frequency of gastrointestinal adverse reactions than patients receiving other opioids [39% (7/18) vs. 26% (110/423) in the 12.5 mg group; 75% (24/32) vs. 34% (142/414) in the 25 mg group]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MOVANTIK. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions : angioedema, rash, and urticaria. Gastrointestinal disorders : Gastrointestinal perforation [see Warnings and Precautions (5.3) ] .

7 DRUG INTERACTIONS Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) : Increased naloxegol concentrations; avoid concomitant use; if unavoidable, reduce dosage to 12.5 mg once daily and monitor for adverse reactions. (2.4 , 7.1) Strong CYP3A4 inducers (e.g., rifampin) : Decreased concentrations of naloxegol; concomitant use is not recommended. (7.1) Other opioid antagonists : Potential for additive effect and increased risk of opioid withdrawal; avoid concomitant use. (7.1) 7.1 Effects of Other Drugs on MOVANTIK Table 2 displays the effects of other drugs on MOVANTIK. Table 2. Effects of Other Drugs on MOVANTIK Concomitant Agent Mechanism of Action Clinical Recommendation CYP3A4 Inhibitors •Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) •Increase plasma naloxegol concentrations and may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ]. •Use with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4) ] . •Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) •Avoid use with moderate CYP3A4 inhibitors; if unavoidable, decrease the dosage of MOVANTIK to 12.5 mg once daily and monitor for adverse reactions [see Dosage and Administration (2.4) ] . •Weak CYP3A4 inhibitors (e.g., quinidine, cimetidine) •Clinically significant increases in naloxegol concentrations are not expected. •No dosage adjustments are necessary. •Grapefruit or grapefruit juice The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength). •Can increase plasma naloxegol concentrations. •Avoid consumption of grapefruit or grapefruit juice during treatment with MOVANTIK [see Dosage and Administration (2.1) ] . CYP3A4 Inducers •Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s Wort) •Significantly decrease plasma naloxegol concentrations and may decrease the efficacy of MOVANTIK [see Clinical Pharmacology (12.3) ] . •Use with strong CYP3A4 inducers is not recommended . Other Drug Interactions •Other opioid antagonists •Potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal. •Avoid use of MOVANTIK with another opioid antagonist.

8 USE IN SPECIFIC POPULATIONS Pregnancy : May precipitate opioid withdrawal in pregnant women and the fetus. (8.1) Lactation : Breastfeeding not recommended. (8.2) Hepatic Impairment : Avoid in severe impairment. (8.7) 8.1 Pregnancy Risk Summary Limited available data with MOVANTIK use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. MOVANTIK may precipitate opioid withdrawal in the pregnant women and the fetus (see Clinical Considerations ) . In animal development studies, no effects on embryo-fetal development were observed following administration of naloxegol in pregnant rats during the period of organogenesis at doses up to 1452 times the human AUC (area under the plasma concentration-time curve) at the maximum recommended human dose. No effects on embryo-fetal development were observed following administration of naloxegol in pregnant rabbits during the period of organogenesis at doses up to 409 times the human AUC at the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal and Fetal/Neonatal adverse reactions The use of MOVANTIK may be associated with opioid withdrawal in the pregnant woman and the fetus. Data Animal Data Oral administration of up to 750 mg/kg/day naloxegol in rats (1452 times the human AUC at the maximum recommended human dose) and 450 mg/kg/day naloxegol in rabbits (409 times the human AUC at the maximum recommended human dose) during the period of organogenesis produced no adverse effects on embryo-fetal development. Oral administration of up to 500 mg/kg/day in rats (195 times the maximum recommended human dose based on body surface area) during the period of organogenesis through lactation produced no adverse effects on parturition or the offspring. 8.2 Lactation There are no data on the presence of naloxegol in human milk, the effects in nursing infants, or the effects on milk production. Naloxegol is present in rat milk (see Data ). Because of the potential for adverse reactions, including opioid withdrawal in breastfed infants, advise women that breastfeeding is not recommended during treatment with MOVANTIK. Data Following oral administration of naloxegol in lactating rats, concentrations of naloxegol in milk were approximately 3- to 4-fold higher than concentrations of naloxegol in maternal plasma. Naloxegol was detected in plasma from pups. 8.4 Pediatric Use The safety and effectiveness of MOVANTIK have not been established in pediatric patients. 8.5 Geriatric Use Of the total number of subjects in clinical studies of MOVANTIK, 11% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. MOVANTIK exposure was higher in elderly healthy Japanese subjects compared to young subjects [see Clinical Pharmacology (12.3) ] . No dosage adjustment is needed in elderly patients. 8.6 Renal Impairment Some subjects with creatinine clearance (CLcr) values <60 mL/minute (i.e., moderate, severe, or end-stage renal disease) 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 12.5 mg once daily is recommended. No dosage adjustment is needed in patients with mild renal impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol has not been evaluated. Avoid use of MOVANTIK 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 [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Limited available data with MOVANTIK use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. MOVANTIK may precipitate opioid withdrawal in the pregnant women and the fetus (see Clinical Considerations ) . In animal development studies, no effects on embryo-fetal development were observed following administration of naloxegol in pregnant rats during the period of organogenesis at doses up to 1452 times the human AUC (area under the plasma concentration-time curve) at the maximum recommended human dose. No effects on embryo-fetal development were observed following administration of naloxegol in pregnant rabbits during the period of organogenesis at doses up to 409 times the human AUC at the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal and Fetal/Neonatal adverse reactions The use of MOVANTIK may be associated with opioid withdrawal in the pregnant woman and the fetus. Data Animal Data Oral administration of up to 750 mg/kg/day naloxegol in rats (1452 times the human AUC at the maximum recommended human dose) and 450 mg/kg/day naloxegol in rabbits (409 times the human AUC at the maximum recommended human dose) during the period of organogenesis produced no adverse effects on embryo-fetal development. Oral administration of up to 500 mg/kg/day in rats (195 times the maximum recommended human dose based on body surface area) during the period of organogenesis through lactation produced no adverse effects on parturition or the offspring.