In a clinical study of patients with OIC a daily dose of 50 mg (twice the recommended dosage), administered over 4 weeks, was associated with an increased incidence of GI adverse reactions, such as abdominal pain, diarrhea and nausea. These adverse reactions frequently occurred within 1-2 days after dosing.
No antidote is known for naloxegol. Dialysis was noted to be ineffective as a means of elimination in a clinical study in patients with renal failure.
If a patient on opioid therapy receives an overdose of naloxegol, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.
MOVANTIK is contraindicated in:
Serious and important adverse reactions described elsewhere in labeling include:
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. 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* 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 | 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% |
| *Adverse reactions occurring in ≥3% of patients receiving MOVANTIK 12.5 mg or 25 mg and at an incidence greater than placebo. |
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].
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.
Use of opioids induces slowing of gastrointestinal motility and transit. Antagonism of gastrointestinal mu-opioid receptors by naloxegol inhibits opioid-induced delay of gastrointestinal transit time.
Effect On Cardiac RepolarizationIn a randomized, double-blind, 4-way cross-over thorough QTc prolongation study with moxifloxacin as a positive control, a single 25 mg therapeutic dose or a 150 mg dose (6 times the maximum recommended dosage) of naloxegol, did not have an effect on the QTc interval compared to placebo. Changes in heart rate, RR, PR, and QRS ECG intervals were similar between placebo and naloxegol 25 or 150 mg.
Exposure Response AnalysisThe exposure-response analysis for adverse events showed that the probability of experiencing abdominal pain increased with increasing naloxegol exposure over the dose range of 12.5 mg to 25 mg once a day. The exposure-response analysis for efficacy conducted using the definition of response in the clinical trials indicated that response was similar over this dose range.
Following oral administration, MOVANTIK is absorbed with peak concentrations (Cmax) 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 tmax 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.
Food EffectsA high-fat meal increased the extent and rate of naloxegol absorption. The Cmax 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.
DistributionThe 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 %).
MetabolismNaloxegol 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, Odemethylation, 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.
ExcretionFollowing oral administration of radio-labelled 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.
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.
MOVANTIK (naloxegol) is available in two strengths:
MOVANTIK (naloxegol) tablets are supplied as:
Store MOVANTIK at 20-25°C (68-77°F). Excursions permitted to 15-30°C (59-86°F).
Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: Aug 2017
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Opioid WithdrawalClusters of symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning have occurred in patients treated with MOVANTIK. 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. 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.
Severe Abdominal Pain And/Or DiarrheaReports 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.
Gastrointestinal PerforationCases 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.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
AdministrationAdvise patients to:
Advise patients to tell their healthcare provider when they start or stop taking any concomitant medications. Strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) are contraindicated with MOVANTIK, and other CYP3A4 enzyme modulating drugs can alter MOVANTIK exposure.
Opioid WithdrawalAdvise patients that clusters of symptoms consistent with opioid withdrawal may occur while taking MOVANTIK, including sweating, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Inform patients taking methadone as therapy for their pain condition that they may be more likely to have gastrointestinal adverse reactions such as abdominal pain and diarrhea that may be related to opioid withdrawal, than patients receiving other opioids.
Severe Abdominal Pain And/Or DiarrheaAdvise patients that symptoms may occur after starting treatment. The patient should discontinue MOVANTIK and contact their healthcare provider if they develop severe abdominal pain and/or diarrhea.
Gastrointestinal PerforationAdvise patients to discontinue MOVANTIK and promptly seek medical attention if they develop unusually severe, persistent or worsening abdominal pain.
PregnancyAdvise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of MOVANTIK during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.
NursingAdvise females who are nursing against breastfeeding during treatment with MOVANTIK due to the potential for opioid withdrawal in nursing infants.
MOVANTIK is a registered trademark of the AstraZeneca group of companies.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisIn a 104-week carcinogenicity study in CD-1 mice, naloxegol was not tumorigenic at oral doses up to 100 mg/kg/day in males and 160 mg/kg/day in females (43 and 27 times the human AUC at the maximum recommended human dose for male and female mice, respectively). In a carcinogenicity study in Sprague-Dawley rats, naloxegol was administered orally at doses of 40, 120, and 400 mg/kg/day for at least 93 weeks. Naloxegol did not cause an increase in tumors in female rats. In male rats, an increase in interstitial (Leydig) cell adenomas in testes was observed at 400 mg/kg/day (818 times the human AUC at the maximum recommended human dose). The no observed effect level for increased tumor incidence was 120 mg/kg/day in male and 400 mg/kg/day in female rats (246 and 1030 times the human AUC at the maximum recommended human dose for male and female rats, respectively). The Leydig cell neoplasms in rats are considered to be unlikely relevant to humans.
MutagenesisNaloxegol was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, mouse lymphoma TK+/-mutation assay, or the in vivo mouse micronucleus assay.
Impairment Of FertilityNaloxegol was found to have no effect on fertility or reproductive performance in male and female rats at oral doses up to 1000 mg/kg/day (greater than 1000 times the human AUC at the maximum recommended human dose).
Use In Specific Populations Pregnancy Pregnancy Category CRisk 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.
Nursing MothersIt 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.
Pediatric UseThe safety and effectiveness of MOVANTIK have not been established in pediatric patients.
Geriatric UseOf 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. No dosage adjustment is needed in elderly patients.
Renal ImpairmentSome 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.
Hepatic ImpairmentThe 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.
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.
Dosage In Adult Patients With Renal ImpairmentThe 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.
Dosage Recommendations Due To Drug InteractionsAvoid 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.
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.
HOW SUPPLIED Dosage Forms And StrengthsMOVANTIK (naloxegol) is available in two strengths:
MOVANTIK (naloxegol) tablets are supplied as:
Store MOVANTIK at 20-25°C (68-77°F). Excursions permitted to 15-30°C (59-86°F).
Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: Aug 2017
Side Effects & Drug Interactions SIDE EFFECTSSerious and important adverse reactions described elsewhere in labeling include:
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. 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* 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 | 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% |
| *Adverse reactions occurring in ≥3% of patients receiving MOVANTIK 12.5 mg or 25 mg and at an incidence greater than placebo. |
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].
DRUG INTERACTIONS Effects Of Other Drugs On MOVANTIKTable 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 | ||
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| CYP3A4 Inducers | ||
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| Other Drug Interactions | ||
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| * 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). |
