Movantik Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

MOVANTIK (naloxegol oxalate) is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with non-cancer pain who have had an inadequate response to laxative(s).

Pediatrics (<18 years of age): The safety and efficacy of MOVANTIK in pediatric patients below 18 years of age has not been established and is not indicated for use in this patient population.

CONTRAINDICATIONS

MOVANTIK (naloxegol oxalate) is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container, or to any other opioid antagonist. For a complete listing of ingredients, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
• Patients with known or suspected gastrointestinal obstruction or in patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation (see WARNINGS AND PRECAUTIONS, Gastrointestinal).
• Patients concomitantly receiving strong CYP3A4 inhibitors (e.g., ketoconazole, voriconazole, clarithromycin, protease inhibitors such as ritonavir), due to significant increase in exposure to naloxegol (see DRUG INTERACTIONS).

WARNINGS AND PRECAUTIONS

General

Opioid withdrawal syndrome: Cases of opioid withdrawal syndrome have been reported in patients treated with MOVANTIK. Opioid withdrawal syndrome is a cluster of three or more of the following signs or symptoms: hyperhidrosis, dysphoric mood, nausea or vomiting, muscle aches, lacrimation or rhinnorrhea, pupillary dilation or piloerection or sweating, diarrhea, yawning, fever or insomnia. If opioid withdrawal syndrome is suspected the patient should discontinue MOVANTIK and contact their healthcare professional (see Neurologic).

Concurrent methadone use: Patients receiving methadone for their pain in clinical trials had a higher frequency of gastrointestinal adverse events (such as abdominal pain and diarrhea) than patients not receiving methadone and, in a few cases, symptoms suggestive of opioid withdrawal when receiving MOVANTIK 25 mg were observed. Interactions: Concomitant use of MOVANTIK with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) can significantly reduce exposure to naloxegol and should generally be avoided (see DRUG INTERACTIONS).

The concomitant use of moderate CYP3A4 inhibitors (e.g. diltiazem, verapamil, erythromycin) should be avoided with MOVANTIK, since the systemic exposure to naloxegol is increased. If this concomitant use is considered absolutely necessary by the physician, the possible benefits of MOVANTIK must clearly outweigh the risk of toxicity due to increase in systemic exposure to MOVANTIK, and it is recommended to use a daily MOVANTIK dose of 12.5 mg with close monitoring for signs of adverse events (e.g., opioid withdrawal syndrome and/or reversal of analgesia). See DRUG INTERACTIONS; DOSAGE AND ADMINISTRATION, Special Populations. Concomitant consumption of grapefruit (a CYP3A4 inhibitor) or grapefruit juice while taking MOVANTIK should be avoided.

Concomitant use of strong CYP3A4 inhibitors is contraindicated (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Cardiovascular

Patients with cardiovascular conditions: MOVANTIK was not studied in the clinical trial program in patients who had a recent history of myocardial infarction within 6

months, symptomatic congestive heart failure, overt cardiovascular disease or patients with a QT interval of ≥ 500msec. MOVANTIK should be used with caution in these patients. A QTc study performed with naloxegol in healthy volunteers did not indicate any prolongation of the QT interval at the intended therapeutic dose (see ACTION AND CLINICAL PHARMACOLOGY, Mechanism of Action and Pharmacodynamics).

Gastrointestinal

Potential for gastrointestinal perforation: Cases of gastrointestinal perforation have been reported in the post-marketing setting including fatal cases when naloxegol was used in patients who were at an increased risk of gastrointestinal perforation. Naloxegol must not be used in patients with known or suspected gastrointestinal obstruction or in patients at an increased risk of recurrent obstruction, or in patients with underlying cancer who are at heightened risk of gastrointestinal perforation. Caution with regards to the use of MOVANTIK should be exercised in patients with any condition which might result in impaired integrity of the gastrointestinal tract wall (e.g., severe peptic ulcer disease, Crohn’s Disease, active or recurrent diverticulitis, infiltrative gastrointestinal tract malignancies or peritoneal metastases) taking into account the overall benefit-risk profile for a given patient. Patients should be advised to discontinue MOVANTIK therapy and promptly notify their physician if they develop unusually severe or persistent abdominal pain.

Severe abdominal pain and/or severe diarrhea: MOVANTIK may cause severe abdominal pain and/or severe diarrhea. Reports of severe abdominal pain and/or severe diarrhea have been observed in clinical trials with the 25 mg dose, typically occurring shortly after initiation of treatment. There was a higher incidence of severe and/or serious adverse events of abdominal pain in patients taking the 25 mg dose compared to placebo (5.6% for naloxegol 25 mg vs. 0.9% placebo) and diarrhea (1.6% for naloxegol 25 mg vs. 1.1% for placebo). Patients should be advised to discontinue therapy if severe symptoms occur, and promptly report severe, persistent or worsening symptoms to their physician.

Hepatic

Severe hepatic impairment: MOVANTIK has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore, the use of MOVANTIK is not recommended in such patients.

Neurologic

Disruptions of the blood-brain barrier: Patients with clinically important disruptions to the blood-brain barrier may be at higher risk for naloxegol entry into the CNS, and opioid withdrawal syndrome or reversal of analgesia. In these patients, MOVANTIK should only be used if the potential benefits clearly outweigh the risks of MOVANTIK, with observation for potential CNS effects, such as Symptoms of opioid withdrawal or reversal of analgesia.

Renal

Renal impairment: As a few patients may experience higher than normal exposure to naloxegol, treatment with MOVANTIK should be discontinued if side effects impacting tolerability occur. The starting daily dose for patients with moderate, severe or end-stage renal impairment is 12.5 mg. If needed and if the 12.5 mg dose is well tolerated, daily the dose can be increased to 25 mg (see DOSAGE AND ADMINISTRATION, Special Populations; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Psychomotor Impairment

No studies have been conducted to assess ability to drive while taking MOVANTIK. MOVANTIK is not expected to have any meaningful influence on the ability to drive or use machines.

Special Populations

Pregnant women: There are no adequate clinical data on the use of MOVANTIK in pregnant women.

The use of MOVANTIK during pregnancy is not recommended due to the risk of opioid withdrawal for the fetus (immature blood brain barrier).

Animal studies do not indicate harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development at exposures in excess of 70 times the human therapeutic exposure. Naloxegol had no effect on fertility in animals (see Part II: TOXICOLOGY).

Nursing women: It is unknown whether naloxegol is excreted in human breast milk, however, naloxegol is excreted in rat milk and absorbed in bursing rat pups. Therefore due to the possible risk of opioid withdrawal in infants, the use of MOVANTIK in nursing women is not recommended.

Pediatrics (<18 years of age): The safety and efficacy of MOVANTIK in pediatric patients below 18 years of age have not been established and is not indicated in this patient population.

Geriatrics (≥65 years of age): Some increase in naloxegol systemic exposure was noted in some elderly subjects (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). No dose adjustment is recommended for the elderly (see ADVERSE REACTIONS; DOSAGE AND ADMINISTRATION, Special Populations).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Across all Phase II/III clinical studies, approximately 1500 patients with non-cancer pain opioid-induced constipation (OIC) were exposed to MOVANTIK. However, only Phase III clinical trials are discussed for safety. The following table summarises the Phase III studies providing the main safety data.

Table 1 Main Phase III clinical studies providing data for the safety evaluation of naloxegol

^a flexible laxative treatment regimen determined by the Investigator according to his/her best clinical judgement. Some of the patients continued from KODIAC 5 and KODIAC 7.

Abbreviations: NGL naloxegol

An additional extension study (KODIAC 7) included 291 patients who were rolled over from the KODIAC 4 study (97 treated with MOVANTIK 25 mg, 94 with MOVANTIK 12.5 mg, and 100 with placebo). Overall 188 patients were exposed to >24-week treatment (63 patients with MOVANTIK 25 mg, 56 with MOVANTIK 12.5 mg, and 63 with placebo groups).

In the two 12-week pivotal placebo-controlled Phase III studies (KODIAC 4 and KODIAC 5), 446 patients received MOVANTIK 25 mg, 441 patients received MOVANTIK 12.5 mg, and 444 received placebo. Overall, treatment-emergent adverse events (AEs) occurred in 52.4%, 63.5% and 51.1% of patients treated with MOVANTIK 12.5 mg, MOVANTIK 25 mg and placebo respectively. The most commonly reported treatment-emergent AEs (reported regardless of causality) with MOVANTIK (≥5%) were abdominal pain, diarrhea, nausea and flatulence (see Table 2). Frequencies and patterns of AEs in the 12-week blinded safety extension study (KODIAC 7) and in the 52-week long-term open-label safety study (KODIAC 8) were generally consistent with those in the 12-week studies, as were the patient’s reasons for requiring opioid medication. Most AEs reported with MOVANTIK were mild to moderate in intensity.

The proportion of patients with discontinuation due to AEs (DAEs) in KODIAC 4 and KODIAC 5 was higher in the MOVANTIK 25 mg group (10.3%) than in the MOVANTIK 12.5 mg (4.8%) and placebo (5.4%) groups. The most common DAEs were due to gastrointestinal AEs: diarrhea, abdominal pain and nausea, and the higher rate of DAEs in the 25 mg group appeared to be driven predominantly by treatment differences in the incidence of diarrhea and abdominal pain DAEs. The incidence and pattern of DAEs in the MOVANTIK 25 mg group in KODIAC 8 (52-week study) was comparable to those seen in the 12-week studies.

The incidence of Serious Adverse Events (SAEs) at any time during the 12-week studies was 5.7%, 3.4% and 5.2% in the MOVANTIK 12.5 mg, MOVANTIK 25 mg and placebo groups respectively. The incidence of SAEs in KODIAC 8 was 9.6% in the MOVANTIK 25 mg group and 11.1% in the standard of care group.

There was a higher incidence of severe and/or serious adverse events of abdominal pain in patients taking the 25 mg dose compared to placebo (5.6% for naloxegol 25 mg vs. 0.9% placebo) and diarrhea (1.6% for naloxegol 25 mg vs. 1.1% for placebo).

Uncommon AEs of opioid withdrawal syndrome were reported (see “Opioid Withdrawal” at the end of “Clinical Trial Adverse Drug Reactions” section).

MOVANTIK (naloxegol oxalate) at doses up to 25 mg once daily was generally well tolerated with most of the adverse events being mild to moderate in intensity in LIR patients with opioid-induced constipation (OIC), in clinical studies up to 52 weeks of treatment.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The most commonly reported (≥5%) adverse drug reactions for MOVANTIK 25 mg across all naloxegol clinical studies were abdominal pain (20.6%, the majority of such events were graded as mild to moderate), diarrhea (11.6%), nausea (9.3%), headache (7.0%), flatulence (6.6%) and vomiting (5.2%). Other adverse drug reactions at a lower frequency were nasopharyngitis (4.3%) and hyperhidrosis (3.2%).

Table 2 presents treatment-emergent AEs (regardless of causality) that occurred in patients from two replicate, randomized, double-blind, placebo-controlled studies of 12 weeks duration (KODIAC 4 and KODIAC 5) in ≥2% of patients treated with MOVANTIK (12.5 mg and 25 mg) where the incidence in patients treated with MOVANTIK was greater than the incidence in placebo-treated patients.

A total of 147 (11%) elderly patients ≥65 years of age with OIC were treated with MOVANTIK in the 12-week Phase III studies. The most common AEs reported in the elderly group were similar to the younger age group. No clinically significant difference was noted as compared to adult patients <65 years of age.

The frequencies and patterns of AEs in patients with baseline laxative inadequate responder (LIR) status were generally comparable to that of the overall safety population.

In the 52-week study (KODIAC 8), the adverse event profile was generally consistent with the short-term studies and there were no important or unexpected differences in the safety and tolerability between the MOVANTIK 25 mg group and the usual care group. The proportion of patients who reported at least 1 adverse event was 72% for the usual care control group, and 82% for the MOVANTIK 25 mg group.

Less Common Clinical Trial Treatment Emergent Adverse Events

Treatment emergent AEs (regardless of causality) that were reported in <2% of patients treated with MOVANTIK and in at least 2 patients in any MOVANTIK dose group and in frequency greater than placebo in the two replicate Phase III 12-week studies are listed below by body system: Cardiac disorders: palpitations, ventricular extrasystoles Eye disorders: dry eye Gastrointestinal disorders: abdominal discomfort, abdominal pain lower, abdominal tenderness, dry mouth, eructation, gastritis, gastroesophageal reflux disease, gastrointestinal pain, toothache General disorders and administration site conditions: asthenia, opioid withdrawal syndrome, feeling jittery, influenza like illness, local swelling, localized edema, peripheral edema, pyrexia Infections and infestations: bronchitis, cellulitis, cystitis, fungal infection, gastroenteritis, gastroenteritis viral, herpes zoster, oral herpes, otitis media, pneumonia, tooth abscess Injury, poisoning and procedural complications: accidental overdose, animal bite, arthropod bite, contusion, excoriation Investigations: blood bicarbonate decreased, blood creatinine increased, blood glucose increased, blood pressure increased, blood thyroid stimulating hormone increased, blood urea increased, hematocrit decreased, hemoglobin decreased, liver function test abnormal, weight decreased, weight increased Metabolism and nutrition disorders: decreased appetite, dehydration, hypercholesterolemia, hyperlipidemia, vitamin D deficiency Musculoskeletal and connective tissue disorders: arthritis, flank pain, musculoskeletal chest pain, myalgia, neck pain, osteoarthritis, osteopenia, synovial cyst Nervous system disorder: migraine, paraesthesia, syncope, tremor Psychiatric disorders: anxiety, nightmare, panic attack Renal and urinary disorders: acute renal failure, micturition urgency, pollakiuria Respiratory, thoracic and mediastinal disorders: asthma, cough, nasal congestion, oropharyngeal pain, paranasal sinus hypersecretion, respiratory tract congestion, rhinorrhea, yawning Skin and subcutaneous tissue disorders: cold sweat, contact dermatitis, erythema, urticaria Vascular disorders: flushing, hot flush, hypertension, hypotension

Opioid Withdrawal

Possible opioid withdrawal, defined as ≥3 adverse reaction 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 KODIAC 4 and KODIAC 5 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 KODIAC 4 and KODIAC 5 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].

Abnormal Hematologic and Clinical Chemistry Findings

Refer to the Less Common Clinical Trial Treatment Emergent Adverse Events section under Investigations and Metabolism and nutritional disorders for information on abnormal hematologic and clinical chemistry findings.

Post-Market Adverse Reactions

The following adverse drug reactions were reported during post-marketing surveillance: gastrointestinal perforation (in patients with increased risk factors for gastrointestinal perforation) and hypersensitivity. Adverse drug reactions are presented by MedDRA System Organ Class in order by preferred term.

DRUG INTERACTIONS

Overview

Naloxegol is a sensitive substrate of CYP3A4 enzyme and a substrate of P-glycoprotein (P-gp) transporter, and CYP3A4 is the major CYP enzyme responsible for the metabolism of naloxegol.

Concomitant use with dual P-gp/strong or moderate CYP3A4 inhibitors, or strong CYP3A4 inhibitors significantly increases naloxegol plasma concentrations. Conversely, concomitant use with strong CYP3A4 inducers or dual P-gp/strong CYP3A4 inducers results in decreased plasma concentrations of naloxegol and should generally be avoided.

Drug-Drug Interactions

Strong CYP3A4 inhibitors

Concomitant use of ketoconazole significantly increased the naloxegol AUC and C_max to 12.9- and 9.6-fold, respectively. Therefore, the concomitant use of strong inhibitors (e.g., clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, or protease inhibitors such as ritonavir) is contraindicated with MOVANTIK (see CONTRAINDICATIONS).

Moderate CYP3A4 inhibitors

Concomitant use of diltiazem significantly increased the naloxegol AUC and C_max to 3.4- and 2.9-fold, respectively. Therefore, the concomitant use of moderate CYP3A4 inhibitors (e.g. diltiazem, verapamil, erythromycin) should be avoided with MOVANTIK. If this concomitant use is considered absolutely necessary by the physician, the possible benefits of MOVANTIK must clearly outweigh the risk of toxicity due to increase in naloxegol systemic exposure, and it is recommended to use a daily MOVANTIK dose of 12.5 mg with close monitoring for signs of adverse events (e.g., opioid withdrawal syndrome and/or reversal of analgesia).

Weak CYP3A4 inhibitors

Concomitant use of quinidine significantly increased the naloxegol AUC and C_max to 1.4- and 2.5-fold respectively. Therefore, the daily dose of MOVANTIK when used concomitantly with a weak CYP3A4 inhibitor (e.g., quinidine or cimetidine) should be 12.5 mg.

Strong CYP3A4 inducers

Concomitant use of rifampin significantly decreased the naloxegol AUC and C_max by 89% and 76%, respectively. Therefore, the use of MOVANTIK concomitantly with a strong CYP3A4 inducer (e.g., carbamazepine, phenytoin or St. John’s Wort) is not recommended.

Dual P-gp/CYP3A4 inhibitor

Dosing recommendations for MOVANTIK used concomitantly with drug products causing both CYP3A4 and P-gp inhibition should be based on CYP3A4 status (strong, moderate or weak, as described in the previous related paragraphs).

Other μ-opioid receptor antagonists: Given the mode of action of naloxegol, as a peripheral μ-opioid receptor antagonist, it should not be concomitantly taken with any other opioid antagonists (e.g., naltrexone, naloxone) due to the potential for an additive effect of opioid receptor antagonism and an increased risk of opioid withdrawal.

In in vitro studies with naloxegol found no significant inhibitory effect on the activity of CYP1A2, CYP2C9, CYP2D6, CYP3A4 or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6 or CYP3A4 were observed. Therefore, naloxegol 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 or OATP1B3.

In a study conducted in healthy subjects, naloxegol did not meaningfully alter the pharmacokinetics of morphine and its major circulating metabolites.

Drug-Food Interactions

A high-fat high-calorie meal increased the extent of naloxegol absorption by 45% as measured by the AUC and the rate of naloxegol absorption by 30% as measured by the C_max. MOVANTIK should be taken in the morning on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours post-meal (see DOSAGE AND ADMINISTRATION, Dosing Considerations; ACTION AND CLINICAL PHAMACOLOGY, Pharmacokinetics).

Grapefruit juice has been classified as a CYP3A4 inhibitor. Concomitant consumption of grapefruit or grapefruit juice while taking MOVANTIK should be avoided (see WARNINGS AND PRECAUTIONS, General).

Drug-Herb Interactions

Concomitant use of St. John’s wort may lead to significant decrease in naloxegol exposure and, therefore, should be avoided (see WARNINGS AND PRECAUTIONS, General; DRUG INTERACTIONS, Drug-Drug Interactions).

Drug-Laboratory Interactions

Interactions with laboratory tests have not been studied.

DOSAGE AND ADMINISTRATION

Dosing Considerations

MOVANTIK (naloxegol oxalate) should be taken in the morning on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours post-meal (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

For patients who are unable to swallow the tablet whole, the MOVANTIK tablet can be crushed to a powder and mixed in half of a glass of room temperature non-carbonated water (120 ml) and drunk immediately. The glass should then be rinsed with a further half glass of room temperature non-carbonated water (120 ml) and the contents drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). When administered via a nasogastric tube a total water volume of 240 ml should be used. The patient should be instructed to perform the following steps:

1. 1. Flush the NG tube with 1 ounce (30 mL) of water using a 60 mL syringe.
2. 2. Crush the tablet to a powder in a container and mix with approximately 2 ounces (60mL) of water.
3. 3. Draw up the mixture using the 60 mL syringe and administer the syringe contents through the NG tube.
4. 4. Add approximately 2 ounces (60 mL) of water to the same container used to prepare the dose of MOVANTIK.

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.

When MOVANTIK therapy is initiated, it is recommended that all currently used maintenance laxative therapy should be stopped, until clinical effect of MOVANTIK is determined.

Recommended Dose and Dosage Adjustment

The recommended dose of MOVANTIK is 25 mg once daily.

Special Populations

Pediatrics (<18 years of age): MOVANTIK is not indicated in children.

Geriatrics (≥65 years of age): No dose adjustment for MOVANTIK is recommended for the elderly (see WARNINGS AND PRECAUTIONS, Special Populations; ADVERSE REACTIONS; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Renal impairment: The starting dose for patients with moderate, severe, or end-stage renal impairment is 12.5 mg. The dose can be increased to 25 mg if the 12.5 mg dose is well tolerated. As a few patients may experience higher than normal exposure to naloxegol, treatment with MOVANTIK should be discontinued if side effects impacting tolerability occur (see WARNINGS AND PRECAUTIONS, Renal; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Hepatic impairment: No dose adjustment for MOVANTIK is required for patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Safety and efficacy of MOVANTIK in patients with severe hepatic impairment (Child-Pugh Class C) have not been established; therefore, the use of MOVANTIK is not recommended in such patients (see WARNINGS AND PRECAUTIONS, Hepatic).

CYP3A4 and P-glycoprotein transporters (P-gp) modulators: Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, voriconazole, clarithromycin, protease inhibitors such as ritonavir) can significantly increase exposure to naloxegol and is contraindicated (see CONTRAINDICATIONS; DRUG INTERACTIONS).

Concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) can significantly reduce exposure to naloxegol and should generally be avoided (see WARNINGS AND PRECAUTIONS, General; DRUG INTERACTIONS).

Concomitant use of moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin) should be avoided with MOVANTIK. If this concomitant use is considered absolutely necessary by the physician, the possible benefits of MOVANTIK must clearly outweigh the risk of toxicity due to increase in naloxegol systemic exposure, and it is recommended to use a daily MOVANTIK dose of 12.5 mg with close monitoring for signs of adverse events (e.g., opioid withdrawal syndrome and/or reversal of analgesia) (see DRUG INTERACTIONS).

The dose of MOVANTIK should be decreased to 12.5 mg once daily when it is concomitantly used with weak CYP3A4 inhibitors (e.g., quinidine, cimetidine) (see DRUG INTERACTIONS).

Dosing recommendations for MOVANTIK used concomitantly with therapeutic products causing both CYP3A4 and P-gp inhibition should be based on CYP3A4 status (strong, moderate or weak, as described in the previous related paragraphs) (see DRUG INTERACTIONS).

Missed Dose

If a patient misses a dose 12 hours or more before the next scheduled dose, the patient should take the missed tablet immediately and then take the next scheduled dose at the normal time.

If a patient misses a dose less than 12 hours before the next scheduled dose, the patient should skip the missed dose and then take the next scheduled dose at the normal time. Patients should be instructed not to take a double dose to make up for a forgotten tablet.

OVERDOSAGE

Signs and Symptoms In a clinical study of patients with OIC, a daily dose of 50 mg was associated with an increased incidence of intolerable gastrointestinal adverse reactions (primarily abdominal pain, diarrhea and/or nausea).

Treatment There is currently no known antidote to reverse the effect of MOVANTIK (naloxegol oxalate). 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 MOVANTIK, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms or reversal of central analgesic effect. In cases of known or suspected overdose of MOVANTIK, symptomatic treatment as well as monitoring of vital functions should be performed.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action and Pharmacodynamics

Physiological effects of opioids in the gastrointestinal tract are caused by binding at opioid receptors within the enteric nervous system and include decreased motility, decreased secretions and increased absorption of fluid from intestines, which may cause constipation in 40-90% of individuals who take opioids.

MOVANTIK (naloxegol oxalate) is a peripherally acting μ-opioid receptor antagonist (PAMORA). Naloxegol is a PEGylated derivative of the μ-opioid receptor antagonist naloxone and antagonizes opioid binding at the peripheral μ-opioid receptors. As a PEGylated derivative of naloxone, the ability of naloxegol to cross the blood brain barrier is limited. Naloxegol acts primarily on the gut μ-opioid receptors and counteracts opioid-induced

constipation (OIC) with limited impact on opioid-mediated analgesic effects on the central nervous system (CNS) at the intended therapeutic doses.

PEGylation reduced the passive permeability of naloxegol and renders it to be a substrate of P-glycoprotein which taken together suggest that CNS penetration of naloxegol is minimal.

In vitro studies demonstrate that naloxegol is a neutral antagonist of μ-opioid receptors (see Part II: DETAILED PHARMACOLOGY).

Dependence/tolerance: MOVANTIK is a peripherally acting μ-opioid receptor antagonist with no known risk of dependency.

Effect on cardiac electrophysiology: In a randomized, double-blind, placebo-controlled, 4-way cross-over thorough ECG study (including QTc prolongation) to assess the effect of a single therapeutic (25 mg) and supratherapeutic (150 mg) dose of naloxegol in healthy male subjects (N=51), naloxegol did not have an effect on QTcF (QTcF= QT/RR^0.33) interval at the 25 mg therapeutic dose. At the supratherapeutic dose of naloxegol 150 mg, the maximum mean difference from placebo in the QTcF interval was 3.1 ms (90% CI 1.3, 4.9) at 1.5 and 2 h post-dosing. Changes in heart rate, RR, PR, and QRS ECG intervals were similar between placebo and naloxegol 25 or 150 mg. The C_max of naloxegol was 37.7 ng/mL at the 25 mg dose and 291 ng/mL at the 150 mg dose.

Pharmacokinetics

Naloxegol demonstrates linear pharmacokinetics. Exposure to naloxegol is approximately dose proportional.

Table 3 Summary of main naloxegol pharmacokinetic parameters in healthy male and female volunteers

Absorption: Following oral administration, naloxegol is absorbed rapidly, with peak concentrations (C_max) achieved in 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.

Naloxegol as a crushed tablet mixed in water, given orally or administered through a nasogastric tube into the stomach demonstrated comparable bioavailability to the whole tablet administered orally with water. The median T_max was 0.75 and 1.50 hours (range 0.23 to 5.02 hours) for the crushed tablet given orally and the crushed tablet given via nasogastic tube, respectively.

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. MOVANTIK should be taken in the morning on an empty stomach, approximately 1 hour prior to the first meal of the day or 2 hours post-meal (see DOSAGE AND ADMINISTRATION, Dosing Considerations).

Distribution: The mean apparent volume of distribution during the terminal phase (Vz/F) in healthy volunteers ranged from 968 to 2140 L across dosing groups and studies. Plasma protein binding of naloxegol in humans was low and the fraction unbound ranged from 80% to 100%.

Metabolism: Naloxegol is mainly metabolized by the CYP3A4 enzyme system. In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine and feces. These metabolites represented more than 32% of the administered dose and were formed via N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain. None of the metabolites were present in >10% of the plasma concentrations of parent or drug related material.

Excretion: Following 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. Thus renal excretion is a minor clearance pathway for naloxegol. In clinical pharmacology studies, the half-life of naloxegol at therapeutic dose ranged from 6 to 11 hours.

Special Populations and Conditions

Pediatrics (<18 years of age): The pharmacokinetics of naloxegol in the pediatric population has not been established and is not indicated in this patient population.

Geriatrics (≥65 years of age): There is a small effect of age on the pharmacokinetics of naloxegol (approximately 0.7% increase in AUC for every year increase in age). No dose adjustment for MOVANTIK is recommended for the elderly.

Elderly healthy Japanese subjects had naloxegol steady state plasma levels (AUC and C_max) that were approximately 50% greater than those obtained in young healthy subjects.

Gender: There is no gender effect on the pharmacokinetics of naloxegol.

Race: In African American subjects, there was an approximately 20% decrease in the AUC and 10% decrease in C_max of naloxegol when compared to Caucasian subjects. In Asian subjects, it was suggested that there was a 30% increase in C_max of naloxegol.

Renal impairment: As renal clearance is a minor route of elimination for naloxegol, regardless of severity (i.e., moderate, severe and end stage renal failure), the impact of renal impairment on the pharmacokinetics of naloxegol was minimal in most subjects. However, in 2 out of 8 patients (in both the moderate and severe renal impairment groups but not in the end stage renal failure group), up to 10-fold increases in the exposure of naloxegol were observed. Exposure of naloxegol in end-stage renal disease patients on hemodialysis was similar to healthy volunteers with normal renal function.

The starting dose for patients with moderate, severe, or end-stage renal impairment is 12.5 mg. The dose can be increased to 25 mg if the 12.5 mg dose is well tolerated. As a few patients may experience higher than normal exposure to naloxegol, treatment with MOVANTIK should be discontinued if side effects impacting tolerability occur (see DOSAGE AND ADMINISTRATION, Special Populations).

Hepatic impairment: Less than 20% decreases in AUC and 10% decreases in C_max were observed in patients with mild and moderate hepatic impairment (Child-Pugh Class A and B). The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol was not evaluated, therefore, the use of MOVANTIK is not recommended in such patients (see WARNINGS AND PRECAUTIONS, Hepatic).

STORAGE AND STABILITY

Store at controlled room temperature (15-30°C).

Keep in a safe place out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

MOVANTIK (naloxegol oxalate) 12.5 mg tablets are oval, biconvex, mauve, film-coated, intagliated with “12.5” on one side and “nGL” on the other side.

MOVANTIK 25 mg tablets are oval, biconvex, mauve, film-coated, intagliated with “25” on one side and “nGL” on the other side.

Composition

MOVANTIK 12.5 mg and 25 mg tablets contain the following non-medicinal ingredients:

Tablet core: mannitol, microcrystalline cellulose, croscarmellose sodium, propyl gallate, magnesium stearate

Tablet coat: hypromellose, titanium dioxide, macrogol 400, iron oxide red, iron oxide black

Packaging

Both strengths of MOVANTIK are available in high-density polyethylene (HDPE) bottles containing desiccant, with a white polypropylene child resistant screw cap. Each pack contains 30 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

CLINICAL TRIALS

Treatment of Opioid-Induced Constipation (OIC)

Table 4 Summary of Pivotal Clinical Trials in OIC

a Patients included in the intent to treat (ITT) analysis set.

Abbreviations: DB Double-blind.

Efficacy Studies

The efficacy of MOVANTIK (naloxegol oxalate) in the treatment of OIC was assessed in two replicate, multicentre, randomized, double-blind, placebo-controlled studies of 12 weeks duration in patients with OIC and non-cancer related pain (see Table 4). Patients taking a minimum of 30 morphine equivalent units (meu) of opioids per day for at least 4 weeks before enrolment and self-reported OIC were eligible to participate. OIC was confirmed through a 2-week run-in period and defined as <3 spontaneous bowel movements (SBMs) per week on average with at least one or more symptoms of straining, hard/lumpy stools and or sensation of incomplete evacuation/anorectal obstruction in at least 25% of bowel movements. Patients with possible clinically important disruption of the blood-brain barrier were excluded. Patients who had a QTcF >500 msec at screening, a recent history of myocardial infarction within 6 months before randomization, symptomatic congestive heart failure, or had any other overt CV disease were also excluded from the clinical studies. In addition, patients with moderate or severe hepatic insufficiency were excluded.

Response to study drug over 12 weeks in patients who had an inadequate response to laxatives in the 2 weeks prior to enrolment was evaluated. The laxative response status was determined at the screening visit using an investigator administered questionnaire (Stool Symptom Screener) about previous laxative use and constipation symptoms over the past 2 weeks. Patients categorized as Laxative Inadequate Responder (LIR) reported to have used a minimum of one class of laxative at least 4 days over the 14 days preceding first study visit and either moderate, severe or very severe intensity of at least one of the following OIC symptoms: incomplete bowel movements, hard stools, straining or sensation of needing to pass a bowel movement but unable to do so.

Throughout the study, patients were prohibited from using laxatives other than bisacodyl rescue laxative if they had not had a bowel movement for 72 hours. An SBM was defined as a bowel movement without rescue laxative taken within the past 24 hours.

A total of 652 patients in KODIAC 4 and 700 patients in KODIAC 5 were randomized to receive 12.5 mg or 25 mg of MOVANTIK or placebo once daily for 12 weeks. The mean age of the subjects was 52 years, 62% were women, 79% were white and 11% were 65 years of age or older. The mean daily opioid morphine equivalent dose was 138 mg/day and patients had been taking opioids for an average of 3.6 years for the current episode of pain. Back pain and arthritis were the most common reasons for pain (57% and 10%, respectively). Laxative use within the 2 weeks prior to enrolment was reported by 71% of patients and by 84% percent within 6 months prior to enrolment. Patients were stratified based on their response to laxative use (LIR, Laxative Adequate Responders (LAR), and Laxative Unknown Responders (LUR)) and were to be randomly assigned to one of the 3 treatment groups in a 1:1:1 ratio. The randomization procedure was designed to ensure that a minimum of 50% of patients in were LIR.

The primary efficacy endpoint was the response over the 12-week treatment period, defined by ≥3 SBMs per week and a change from baseline of ≥1 SBM per week for at least 9 out of the 12 treatment weeks including 3 out of the last 4 treatment weeks. The first of three multiplicity protected secondary endpoints was the 12-week responder rate in the LIR subgroup.

Study results: Results across the confirmatory studies demonstrated durability and consistency of efficacy for MOVANTIK in the treatment for OIC. In both studies, 54% of the patients were categorized as LIR. LIR patients treated with MOVANTIK 25 mg demonstrated statistically significant higher rate of response, as compared to placebo in both studies. MOVANTIK 12.5 mg demonstrated a statistically significant difference in the response rate over placebo in KODIAC 4 only (see Table 5).

There was no definitive evidence for differential effects of age, gender, or weight on efficacy of MOVANTIK. The subjects who participated in KODIAC 4 and KODIAC 5 were taking a wide-range of opioids.

A response analysis identical to the primary efficacy analysis except for using complete spontaneous bowel movement (CSBM) instead of SBM showed that in the pooled KODIAC 4 and 5 studies, the response rate was larger with MOVANTIK 25 mg (20.7%), as compared to placebo (9.6%), for a difference of 11.1% (p-value=0.001).

Among LIR patients on MOVANTIK 25 mg, approximately 54% (61% in KODIAC 4 and 48% in KODIAC 5) of patients had an SBM within 12 hours of the first dose.

Furthermore, results from secondary endpoints (mean SBM’s per week, mean days per week with at least 1 SBM, mean degree of straining and mean stool consistency), generally supported the findings from the primary endpoint and the benefit of MOVANTIK for OIC in patients with non-cancer pain and who are inadequate responders to laxative(s).

There were no clinically relevant differences between MOVANTIK and placebo in average pain intensity or in clinically important changes in daily opioid dose over the 12 week studies.

DETAILED PHARMACOLOGY

Non-Clinical Pharmacology

Primary pharmacodynamics: The pharmacological profile of naloxegol was characterised in in vitro binding assays demonstrating that naloxegol binds to μ-, δ- and κ- opioid receptors, with highest affinity at μ-opioid receptors. In [³⁵S]GTPγS binding assays, naloxegol was shown to be a full and competitive antagonist at human μ-opioid receptors, with no significant agonist efficacy. In addition, in vitro binding data indicate that naloxegol also is an antagonist of δ-opioid receptors, and it is a weak κ-opioid receptor partial agonist. However, naloxegol does not show any signs of κ-opioid agonism in a more physiological system (rabbit vas deference assay). In in vivo studies naloxegol was shown to reverse morphine-induced slowing of gastrointestinal transit at doses lower than those that reverse morphine analgesia, providing evidence of a separation between desired peripheral gastrointestinal effect and undesired CNS morphine antagonism in rats.

Secondary pharmacodynamics: Naloxegol was tested in a diverse panel of 327 targets covering a broad spectrum of receptors, ion channels and enzymes. Significant activity was only seen at the to μ-, δ- and κ- opioid receptors.

Safety pharmacology: Naloxegol had no effects in assays for general behavioral effects, proconvulsive activity, analgesic activity and abuse potential, suggesting that naloxegol is unlikely to cause any CNS-mediated adverse events in man. These results also indicate a low likelihood of an opioid abuse liability. Naloxegol had an IC₅₀ >300 μM at the hERG ion channel and was inactive against further 7 cardiac channels. Cardiovascular effects were seen in a dog telemetry study where naloxegol caused non dose-related transient decreases in both systolic and diastolic blood pressure, left ventricular systolic pressure and indexes of cardiac myocardial contractility and relaxation. Heart rate was also slightly increased. The No Observed Effect Level (NOEL) for the decreases in arterial blood pressure, left ventricular systolic pressure, and cardiac contractility and relaxation was 5 mg/kg, with maximum exposures comparable to the human exposure (C_max) at the recommended human dose (RHD) of 25 mg/day. The telemetry findings in the dog study are unlikely to be clinically relevant. No cardiovascular effects were observed on canine myocyte contractility at up to 100 µM or in a rat heart Langendorff preparation at up to 10 μM.

The lack of effect of naloxegol on cardiac ion channels and cardiac myocytes, as well as the absence of cardiovascular effects in repeat-dose toxicology studies, indicate that naloxegol is unlikely to have a direct effect on the heart or ECG parameters.

Rat plethysmography, gastric emptying/intestinal transport and renal function studies indicated that naloxegol is unlikely to have any adverse effect on the respiratory system, gastrointestinal or renal systems at the RHD.

Pharmacokinetics: Absorption, distribution, metabolism, and excretion (ADME) properties of naloxegol were investigated in vitro (in Caco-2 cells, hepatocytes and brain tissues) and in vivo (in mouse, rat, dog, non-human primate and human). Naloxegol is considered to be a low permeability molecule. The in vitro unbound fraction of naloxegol in plasma ranged from 47% to 100% across species. Brain perfusion studies demonstrated a slower rate of entry into the brain for naloxegol (4.1 pmol/g brain/sec), similar to the slow permeation reference atenolol (5.17 pmol/g brain/sec), compared to naloxone (60.2 pmol/g brain/sec). Low brain penetration potential was further confirmed in a rat quantitative whole-body autoradiography study. In rat, biliary excretion contributed substantially to the elimination of ¹⁴C-naloxegol following a single oral administration. In vitro, naloxegol appears to be a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein, and appears to have low potential to inhibit cytochrome P450 enzymes (CYPs). In vitro metabolism investigations using hepatocytes demonstrated the similarity in metabolic pathways across all species tested, and all metabolites observed in human hepatocytes have also been observed in animal hepatocytes.

TOXICOLOGY

Animal toxicology

Most of the effects observed in the pivotal repeat dose toxicity studies in the two main toxicology species, the rat and dog, and the mouse as a second rodent species for carcinogenicity assessment, were generally limited to effects on body weight and food consumption as well as stress-related findings which occurred at dose levels above the NOAEL and generally at doses at or close to the maximum tolerated dose level. Whilst most findings in the repeat dose toxicity studies were likely not to relate to inhibition of opioid receptor signaling, a dose-related finding of soft stool/diarrhea in the dog may reflect exaggerated pharmacological effects. Some findings, such as ataxia, tremors and hypoactive behaviour seen at high doses in the dog, were likely to be indicative of CNS exposure. The only target organ of toxicity identified across all main toxicity species was the liver (weight increase and hypertrophy in rats, weight increase in dogs), but these findings were slight, not adverse and reversible. Safety pharmacology endpoints were included in the repeat-dose toxicology studies, with cardiovascular endpoints assessed in all dog studies. There were no adverse effects observed on blood pressure and ECG parameters (including heart rate and QTcV, single time-point/registration occasion) in dogs at doses up to 200 mg/kg/day.

The NOAEL in the chronic rat (6-month) and dog (9-month) toxicity studies was 200 mg/kg/day with exposure multiples of at least 248x (rat) and 165x (dog) the human exposure at the RHD. Thus, findings in the repeat dose studies only occur at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Carcinogenesis

Carcinogenicity studies of naloxegol were conducted in Sprague-Dawley rats and CD-1 mice. In a 104-week study in CD-1 mice, naloxegol was not carcinogenic. Naloxegol was administered orally to rats at doses of 40, 120, and 400 mg/kg/day for at least 93 weeks. Naloxegol did not cause an increase in tumours in female rats. In male rats, a dose-related increase in Leydig cell adenomas and interstitial cell hyperplasia was observed at 120 mg/kg/day and above. A dose-related decrease in the incidence of pituitary adenomas was noted in male rats at 400 mg/kg/day and female rats at 120 mg/kg/day and above. A dose-related decrease in the incidence of mammary carcinomas in females was noted at 120 mg/kg/day and above. The no observed effect level for increased tumour incidence was 40 mg/kg/day in male and 400 mg/kg/day in female rats (51 (males) and 1030 (females) times the human exposure (AUC) at the RHD of 25 mg/day. The observed neoplastic changes are well known hormonal and centrally mediated effects in the rat which are not relevant for humans.

Mutagenesis

The genotoxic potential of naloxegol was evaluated in a battery of in vitro and in vivo test systems. Naloxegol did not show any mutagenic activity in a bacterial mutation (Ames) test. Naloxegol did not induce mutations in the mouse Lymphoma TK assay or chromosome damage in the in vivo mouse micronucleus test. The overall weight of evidence for naloxegol supports the conclusion that this compound is not genotoxic and does not represent a carcinogenic risk to man.

Reproduction and Development

Naloxegol was found to have no effect on fertility of male and female rats at oral doses up to 1000 mg/kg per day (greater than 1000 times the human therapeutic exposure (AUC) at the recommended human dose of 25 mg/day). Naloxegol had no effect on fetal development at oral doses up to 750 mg/kg per day in rats (1452 times the human exposure (AUC) at the recommended human dose of 25 mg/day) and up to 150 mg/kg per day in rabbits (79 times the human exposure (AUC) at the recommended human dose of 25 mg/day). Naloxegol had no effects on parturition or postnatal development in rats at exposures equivalent to 225 times the human exposure (C_max) at the recommended human dose of 25 mg/day). The relevance of the observed developmental effects observed in the rat and rabbit to human safety is considered negligible since they occurred at maternal exposures that are clinically irrelevant.

REFERENCES

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3. 3. Webster L, Dhar S, Eldon M et al. A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation. Pain 2013;154:1542-50.
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