Naloxegol Oxalate

1 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)

2 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) ] .

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) ] .

12.3 Pharmacokinetics Absorption Following oral administration, MOVANTIK is absorbed with peak concentrations (C max ) achieved at less than 2 hours. In a majority of subjects, a secondary plasma concentration peak of naloxegol was 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) increased in a dose-proportional or almost dose-proportional manner. Accumulation was minimal following multiple daily doses of naloxegol. MOVANTIK as a crushed tablet mixed in water, given orally or administered through a nasogastric tube into the stomach, provides systemic naloxegol concentrations that are comparable to the whole tablet, with a median t max of 0.75 and 1.5 hours (range 0.25 to 5 hours) for the crushed tablet given orally and the crushed tablet given via nasogastric (NG) tube, respectively [see Dosage and Administration (2.2) ] . Food Effects A high-fat meal increased the extent and rate of naloxegol absorption. The C max and AUC were increased by approximately 30% and 45%, respectively. In clinical trials, naloxegol was dosed on an empty stomach approximately 1 hour prior to the first meal in the morning. Distribution The mean apparent volume of distribution during the terminal phase (Vz/F) in healthy volunteers ranged from 968 L to 2140 L across dosing groups and studies. Plasma protein binding of naloxegol in humans was low (~4.2%). Metabolism Naloxegol is metabolized primarily by the CYP3A enzyme system. In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine, and feces. These metabolites were 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. Excretion Following oral administration of radio-labeled 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. Specific Populations Renal Impairment : The effect of renal impairment on the pharmacokinetics of a 25 mg single oral dose of MOVANTIK was studied in subjects with renal impairment (RI) classified as moderate (n=8), severe (n=4), or end-stage renal disease (ESRD) not yet on dialysis (n=4), and compared with healthy subjects (n=6). Most renal impairment (RI) subjects (6 out of 8 with moderate RI, 3 out of 4 with severe RI, and 3 out of 4 with ESRD) had plasma naloxegol pharmacokinetics comparable to those in healthy subjects. The remaining individuals with renal impairment demonstrated higher naloxegol exposures (up to 10-fold) compared to the control group. The reason for these high exposures is unknown. This study also included 8 ESRD patients on hemodialysis. Plasma concentrations of naloxegol in these subjects were similar to healthy volunteers with normal renal function, when MOVANTIK was administered either pre- or post-hemodialysis [see Dosage and Administration (2.3) , Use in Specific Populations (8.6) , and Overdosage (10) ] . Hepatic Impairment: Slight decreases in 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 MOVANTIK. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol was not evaluated [see Use in Specific Populations (8.7) ] . Age: The mean C max , ss and AUC τ,ss 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). Gender: There is no gender effect on the pharmacokinetics of naloxegol. Race: When compared to Caucasian subjects, naloxegol AUC was approximately 20% lower in Blacks and C max was approximately 10% lower and 30% higher in Blacks and Asians, respectively. Drug Interaction Studies Effect of MOVANTIK on Other Drugs In in vitro studies at clinically relevant concentrations, naloxegol did not show a significant inhibitory effect on the activity of CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP3A4 or CYP2C19, nor a significant induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4. Therefore, MOVANTIK is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Naloxegol is not a significant inhibitor of P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. In healthy subjects receiving morphine 5 mg/70 kg intravenously, single doses of MOVANTIK ranging from 8 mg to 1000 mg were given concomitantly with 5 to 6 subjects per dose cohort. With increasing MOVANTIK dose, there was no increasing or decreasing trend in morphine exposure compared to morphine administered alone. An analysis of the pooled data indicated that MOVANTIK had no meaningful impact on the systemic exposure of morphine and its major circulating metabolites. Effect of Other Drugs on MOVANTIK Naloxegol is metabolized mainly by CYP3A enzymes and is a substrate of P-gp transporter. The effects of co-administered drugs on the pharmacokinetics of naloxegol are summarized in Figure 1 [see Drug Interactions (7.1) ] . The effects of once daily oral dosing of 400 mg ketoconazole, once daily oral dosing of 600 mg rifampicin and once daily oral dosing of 240 mg diltiazem (as an extended release formulation) on the pharmacokinetics of 25 mg MOVANTIK were studied following multiple dosing and at steady state exposure of the perpetrator drugs. The effects of 600 mg oral dosing of quinidine and intravenous morphine (5 mg/70 kg) on the pharmacokinetics of 25 mg MOVANTIK were studied following single dosing of the perpetrator drugs. Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Naloxegol *Quinidine due to its effect on P-gp transporter increased naloxegol C max by 2.5-fold; the AUC increased by 1.4-fold; no dosage adjustment is necessary. No drug interaction studies have been conducted for MOVANTIK with drugs that alter gastric pH (e.g., antacids, proton-pump inhibitors). Simulations using physiologically based pharmacokinetic modeling, suggested that naloxegol exposures after co-administration of a single oral 25 mg dose of MOVANTIK with a moderate CYP3A inducer efavirenz (400 mg once a day) are similar to those after 12.5 mg MOVANTIK alone. Figure 1