2.1 Administration

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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.

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Alteration in analgesic dosing regimen prior to initiating MOVANTIK is not required.

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MOVANTIK has been shown to be efficacious in patients who have taken opioids for at least 4 weeks. Sustained exposure to opioids prior to starting MOVANTIK may increase the patient's sensitivity to the effects of MOVANTIK [ see Clinical Studies (14)].

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Take MOVANTIK on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal.

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Swallow tablets whole, do not crush or chew.

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Avoid consumption of grapefruit or grapefruit juice during treatment with MOVANTIK.

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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)].

5.1 Gastrointestinal Perforation

Cases of gastrointestinal perforation have been reported with use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). 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 [see Contraindications (4)].

5.2 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.

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.

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].

7.1 Effects of Other Drugs on MOVANTIK

Table 2 displays the effects of other drugs on MOVANTIK.

8.1 Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with MOVANTIK in pregnant women. The use of MOVANTIK during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. 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. MOVANTIK should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

8.3 Nursing Mothers

It is unknown whether MOVANTIK is present in human milk; however, naloxegol is present in rat milk and is absorbed in nursing rat pups. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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 percent were 65 and over, while 2 percent 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 eva luated. 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)].