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NALOXEGOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Naloxegol is an opioid antagonist used to treat opioid-induced constipation in adults with chronic noncancer pain.

Specific Substances

    1) Pegylated naloxol
    2) NKTR-118
    3) CAS 854601-70-0
    1.2.1) MOLECULAR FORMULA
    1) C34H53NO11-C2H2O4 (Prod Info MOVANTIK(TM) oral tablets, 2014)

Available Forms Sources

    A) FORMS
    1) Naloxegol is available as 12.5 mg and 25 mg tablets (Prod Info MOVANTIK(TM) oral tablets, 2014).
    B) USES
    1) Naloxegol is an opioid antagonist used to treat opioid-induced constipation in adults with chronic noncancer pain (Prod Info MOVANTIK(TM) oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Naloxegol is used to treat opioid-induced constipation in adults with chronic noncancer pain.
    B) PHARMACOLOGY: Naloxegol is a mu-opioid receptor antagonist derivative of naloxone that is specific to peripheral tissues (eg, gastrointestinal tract) due to pegylation that decreases passive permeability and CNS penetration at recommended dosages.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (3% AND GREATER): Abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, and hyperhidrosis. OTHER EFFECTS: Joint pain, nasopharyngitis, bronchitis, and withdrawal symptoms.
    2) DRUG INTERACTION: Concurrent use of naloxegol and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin) or moderate CYP3A4 inhibitors (eg, diltiazem, erythromycin, verapamil) can increase plasma concentration of naloxegol and increase the risk of adverse effects. Concurrent use of naloxegol and grapefruit or grapefruit juice can also increase plasma concentration of naloxegol and increase the risk of adverse effects. Concurrent use of naloxegol and another opioid antagonist can result in an additive effect of opioid receptor antagonism and increase the risk of opioid withdrawal.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Abdominal pain, diarrhea, and nausea have been reported in patients receiving twice the recommended dose of naloxegol. The overdose effects of naloxogel on opioid-naive patients are unknown.
    0.2.20) REPRODUCTIVE
    A) Naloxegol is classified as pregnancy category C. There are no adequate and well-controlled studies of naloxegol use in pregnant women. Because of the immature fetal blood brain barrier, naloxegol use during pregnancy may precipitate opioid withdrawal in the fetus. Due to the lack of human safety information, naloxegol should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, human carcinogenicity studies have not been conducted.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Monitor patients for symptoms of opioid withdrawal (eg, chills, rhinorrhea, diaphoresis or reversal of central analgesic effect).
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Dialysis is ineffective for removal of naloxegol.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged home if psychiatrically stable.
    3) ADMISSION CRITERIA: Hospital admission is rarely necessary. Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) If significant toxicity develops, other causes should be sought. When managing a suspected naloxegol overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Tmax: Less than 2 hours, with a second peak at about 0.4 to 3 hours later. Protein binding: 4.2%. Vd: 968 to 2140 L. Metabolism: Primary metabolism occurs via CYP3A. Excretion: Renal: Naloxegol was 16% recovered in the urine. Recovery of the parent drug in the urine was less than 6% of the total dose. Feces: Oral naloxegol was 68% eliminated in the feces; 16% of that was unchanged and the rest was accounted for by metabolites. Elimination half-life: 6 to 11 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that can cause abdominal pain, nausea, vomiting, and diarrhea.

Range Of Toxicity

    A) TOXICITY: In one study, gastrointestinal adverse effects (eg, abdominal pain, diarrhea, and nausea) developed in patients with opioid-induced constipation within 1 to 2 days of using naloxegol 50 mg daily (twice the recommended dosage). In a randomized, double-blind, 4-way cross-over thorough QTc prolongation study, 150 mg of oral naloxegol (6 times the recommended dosage) resulted in no prolongation of cardiac intervals. No other adverse results were described.
    B) THERAPEUTIC DOSE: ADULT: 12.5 to 25 mg orally once daily. CHILD: Safety and efficacy of naloxegol have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Naloxegol is used to treat opioid-induced constipation in adults with chronic noncancer pain.
    B) PHARMACOLOGY: Naloxegol is a mu-opioid receptor antagonist derivative of naloxone that is specific to peripheral tissues (eg, gastrointestinal tract) due to pegylation that decreases passive permeability and CNS penetration at recommended dosages.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (3% AND GREATER): Abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, and hyperhidrosis. OTHER EFFECTS: Joint pain, nasopharyngitis, bronchitis, and withdrawal symptoms.
    2) DRUG INTERACTION: Concurrent use of naloxegol and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin) or moderate CYP3A4 inhibitors (eg, diltiazem, erythromycin, verapamil) can increase plasma concentration of naloxegol and increase the risk of adverse effects. Concurrent use of naloxegol and grapefruit or grapefruit juice can also increase plasma concentration of naloxegol and increase the risk of adverse effects. Concurrent use of naloxegol and another opioid antagonist can result in an additive effect of opioid receptor antagonism and increase the risk of opioid withdrawal.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Abdominal pain, diarrhea, and nausea have been reported in patients receiving twice the recommended dose of naloxegol. The overdose effects of naloxogel on opioid-naive patients are unknown.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) NASOPHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) In a 52-week, multicenter, open-label, randomized, parallel-group phase 3 study, 804 patients with noncancer pain and opioid-induced constipation who were taking 30 to 1000 morphine-equivalent units per day for 4 weeks or longer, were randomly (2:1) assigned to either receive naloxegol 25 mg/day (n=534) or usual-care (UC; investigator chosen laxative regimen; n=270). Nasopharyngitis developed in 6.2% of patients receiving naloxegol 25 mg/day and 5.6% of patients receiving UC (Webster et al, 2014).
    B) BRONCHITIS
    1) WITH THERAPEUTIC USE
    a) In a 52-week, multicenter, open-label, randomized, parallel-group phase 3 study, 804 patients with noncancer pain and opioid-induced constipation who were taking 30 to 1000 morphine-equivalent units per day for 4 weeks or longer, were randomly (2:1) assigned to either receive naloxegol 25 mg/day (n=534) or usual-care (UC; investigator chosen laxative regimen; n=270). Bronchitis developed in 5.6% of patients receiving naloxegol 25 mg/day and 4.4% of patients receiving UC (Webster et al, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In two double-blind, placebo-controlled trials of 1331 patients with opioid-induced constipation and non-cancer related pain, headache developed in 4% of patients (n=446) receiving naloxegol 25 mg, 4% of patients (n=441) receiving naloxegol 12.5 mg, and 3% of patients (n=444) receiving placebo (Prod Info MOVANTIK(TM) oral tablets, 2014).
    b) In a 52-week, multicenter, open-label, randomized, parallel-group phase 3 study, 804 patients with noncancer pain and opioid-induced constipation who were taking 30 to 1000 morphine-equivalent units per day for 4 weeks or longer, were randomly (2:1) assigned to either receive naloxegol 25 mg/day (n=534) or usual-care (UC; investigator chosen laxative regimen; n=270). Headache developed in 9% of patients receiving naloxegol 25 mg/day and 4.8% of patients receiving UC (Webster et al, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) Patients with conditions that may be associated with localized or diffuse reduction in the structural integrity of the gastrointestinal tract wall (eg, peptic ulcer disease, Ogilvie's syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies, or peritoneal metastases) have developed gastrointestinal perforation following the use of another peripherally acting opioid antagonist (Prod Info MOVANTIK(TM) oral tablets, 2014).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In two double-blind, placebo-controlled trials of 1331 patients with opioid-induced constipation and non-cancer related pain, abdominal pain developed in 21% of patients (n=446) receiving naloxegol 25 mg, 12% of patients (n=441) receiving naloxegol 12.5 mg, and 7% of patients (n=444) receiving placebo (Prod Info MOVANTIK(TM) oral tablets, 2014).
    b) In a 52-week, multicenter, open-label, randomized, parallel-group phase 3 study, 804 patients with noncancer pain and opioid-induced constipation who were taking 30 to 1000 morphine-equivalent units per day for 4 weeks or longer, were randomly (2:1) assigned to either receive naloxegol 25 mg/day (n=534) or usual-care (UC; investigator chosen laxative regimen; n=270). Abdominal pain developed in 17.8% of patients receiving naloxegol 25 mg/day and 3.3% of patients receiving UC. Upper abdominal pain developed in 5.1% of patients (n=534) receiving naloxegol 25 mg/day and 1.1% of patients receiving UC (Webster et al, 2014).
    2) WITH POISONING/EXPOSURE
    a) Abdominal pain has been reported in patients receiving twice the recommended dose of naloxegol (Prod Info MOVANTIK(TM) oral tablets, 2014).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In two double-blind, placebo-controlled trials of 1331 patients with opioid-induced constipation and non-cancer related pain, diarrhea developed in 9% of patients (n=446) receiving naloxegol 25 mg, 6% of patients (n=441) receiving naloxegol 12.5 mg, and 5% of patients (n=444) receiving placebo (Prod Info MOVANTIK(TM) oral tablets, 2014).
    b) In a 52-week, multicenter, open-label, randomized, parallel-group phase 3 study, 804 patients with noncancer pain and opioid-induced constipation who were taking 30 to 1000 morphine-equivalent units per day for 4 weeks or longer, were randomly (2:1) assigned to either receive naloxegol 25 mg/day (n=534) or usual-care (UC; investigator chosen laxative regimen; n=270). Diarrhea developed in 12.9% of patients receiving naloxegol 25 mg/day and 5.9% of patients receiving UC (Webster et al, 2014).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea has been reported in patients receiving twice the recommended dose of naloxegol (Prod Info MOVANTIK(TM) oral tablets, 2014).
    D) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In two double-blind, placebo-controlled trials of 1331 patients with opioid-induced constipation and non-cancer related pain, nausea developed in 8% of patients (n=446) receiving naloxegol 25 mg, 7% of patients (n=441) receiving naloxegol 12.5 mg, and 5% of patients (n=444) receiving placebo (Prod Info MOVANTIK(TM) oral tablets, 2014).
    b) In a 52-week, multicenter, open-label, randomized, parallel-group phase 3 study, 804 patients with noncancer pain and opioid-induced constipation who were taking 30 to 1000 morphine-equivalent units per day for 4 weeks or longer, were randomly (2:1) assigned to either receive naloxegol 25 mg/day (n=534) or usual-care (UC; investigator chosen laxative regimen; n=270). Nausea developed in 9.4% of patients receiving naloxegol 25 mg/day and 4.1% of patients receiving UC (Webster et al, 2014).
    2) WITH POISONING/EXPOSURE
    a) Nausea has been reported in patients receiving twice the recommended dose of naloxegol (Prod Info MOVANTIK(TM) oral tablets, 2014).
    E) VOMITING
    1) WITH THERAPEUTIC USE
    a) In two double-blind, placebo-controlled trials of 1331 patients with opioid-induced constipation and non-cancer related pain, vomiting developed in 5% of patients (n=446) receiving naloxegol 25 mg, 3% of patients (n=441) receiving naloxegol 12.5 mg, and 4% of patients (n=444) receiving placebo (Prod Info MOVANTIK(TM) oral tablets, 2014).
    F) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) In two double-blind, placebo-controlled trials of 1331 patients with opioid-induced constipation and non-cancer related pain, flatulence developed in 6% of patients (n=446) receiving naloxegol 25 mg, 3% of patients (n=441) receiving naloxegol 12.5 mg, and 3% of patients (n=444) receiving placebo (Prod Info MOVANTIK(TM) oral tablets, 2014).
    b) In a 52-week, multicenter, open-label, randomized, parallel-group phase 3 study, 804 patients with noncancer pain and opioid-induced constipation who were taking 30 to 1000 morphine-equivalent units per day for 4 weeks or longer, were randomly (2:1) assigned to either receive naloxegol 25 mg/day (n=534) or usual-care (UC; investigator chosen laxative regimen; n=270). Flatulence developed in 6.9% of patients receiving naloxegol 25 mg/day and 1.1% of patients receiving UC (Webster et al, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) HYPERHIDROSIS
    1) WITH THERAPEUTIC USE
    a) In two double-blind, placebo-controlled trials of 1331 patients with opioid-induced constipation and non-cancer related pain, hyperhidrosis developed in 3% of patients (n=446) receiving naloxegol 25 mg, less than 1% of patients (n=441) receiving naloxegol 12.5 mg, and less than 1% of patients (n=444) receiving placebo (Prod Info MOVANTIK(TM) oral tablets, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a 52-week, multicenter, open-label, randomized, parallel-group phase 3 study, 804 patients with noncancer pain and opioid-induced constipation who were taking 30 to 1000 morphine-equivalent units per day for 4 weeks or longer, were randomly (2:1) assigned to either receive naloxegol 25 mg/day (n=534) or usual-care (UC; investigator chosen laxative regimen; n=270). Arthralgia developed in 6.2% of patients receiving naloxegol 25 mg/day and 5.9% of patients receiving UC (Webster et al, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Naloxegol is classified as pregnancy category C. There are no adequate and well-controlled studies of naloxegol use in pregnant women. Because of the immature fetal blood brain barrier, naloxegol use during pregnancy may precipitate opioid withdrawal in the fetus. Due to the lack of human safety information, naloxegol should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies, no embryofetal development effects were observed in the offspring of rats and rabbits when rats were administered naloxegol doses up to 750 mg/kg/day (1452 times the human AUC at the maximum recommended human dose) and rabbits were administered naloxegol doses up to 450 mg/kg/day (409 times the human AUC at the maximum recommended human dose) during organogenesis. No adverse effects on parturition or the offspring were observed following the oral administration of up to 500 mg/kg/day of naloxegol (195 times the maximum recommended human dose based on body surface area) to rats during organogenesis through lactation (Prod Info MOVANTIK(TM) oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Naloxegol is classified as pregnancy category C (Prod Info MOVANTIK(TM) oral tablets, 2014).
    2) There are no adequate and well-controlled studies of naloxegol use in pregnant women. Because of the immature fetal blood brain barrier, naloxegol use during pregnancy may precipitate opioid withdrawal in the fetus. Due to the lack of human safety information, naloxegol should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus (Prod Info MOVANTIK(TM) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) No human lactation data are available; however, naloxegol is present in rat milk and is absorbed in nursing rat pups. Because of the potential for opioid withdrawal or other serious reactions in nursing infants, it is recommended to discontinue nursing or to discontinue naloxegol in the nursing mother. The importance of therapy to the mother should be taken into consideration (Prod Info MOVANTIK(TM) oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: In animal studies, no fertility or reproductive performance effects were observed in male and female rats following the administration of naloxegol oral doses up to 1000 mg/kg/day (greater than 1000 times the human AUC at the maximum recommended human dose) (Prod Info MOVANTIK(TM) oral tablets, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, human carcinogenicity studies have not been conducted.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, human carcinogenicity studies have not been conducted.
    3.21.4) ANIMAL STUDIES
    A) ADENOMAS IN TESTES
    1) In a 104-week animal study, no tumors developed in CD-1 mice following oral doses up to 100 mg/kg/day in males and 160 mg/kg/day in females (43 and 27 times the human AUC a the maximum recommended human dose for male and female mice, respectively). Naloxegol 40, 120, and 400 mg/kg/day administered orally to Sprague-Dawley rats for at least 93 weeks did not cause an increase in tumors in female rats; however, in Sprague-Dawley male rats, the administration of naloxegol 400 mg/kg/day orally (818 times the human AUC at the maximum recommended human dose) resulted in an increase in interstitial (Leydig) cell adenomas in testes. Naloxegol 120 mg/kg/day and 400 mg/kg/day were considered the no observed effect level for increased tumor incidence in male and female rats, respectively (Prod Info MOVANTIK(TM) oral tablets, 2014).

Genotoxicity

    A) Based on the results of the in vitro bacterial reverse mutation (Ames) assay, mouse lymphoma TK+/- mutation assay, or the in vivo mouse micronucleus assay, naloxegol was not genotoxic (Prod Info MOVANTIK(TM) oral tablets, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Hospital admission is rarely necessary. Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged home if psychiatrically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Monitor patients for symptoms of opioid withdrawal (eg, chills, rhinorrhea, diaphoresis or reversal of central analgesic effect).
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs following significant overdose.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Monitor patients for symptoms of opioid withdrawal (eg, chills, rhinorrhea, diaphoresis or reversal of central analgesic effect).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Dialysis is ineffective for removal of naloxegol (Prod Info MOVANTIK(TM) oral tablets, 2014).
    2) The mean apparent plasma clearance of naloxegol was 88.9 L/hr in patients with ESRD on hemodialysis following administration of naloxegol 25 mg 2 hours prior to hemodialysis (Bui et al, 2014).

Range Of Toxicity

Summary

    A) TOXICITY: In one study, gastrointestinal adverse effects (eg, abdominal pain, diarrhea, and nausea) developed in patients with opioid-induced constipation within 1 to 2 days of using naloxegol 50 mg daily (twice the recommended dosage). In a randomized, double-blind, 4-way cross-over thorough QTc prolongation study, 150 mg of oral naloxegol (6 times the recommended dosage) resulted in no prolongation of cardiac intervals. No other adverse results were described.
    B) THERAPEUTIC DOSE: ADULT: 12.5 to 25 mg orally once daily. CHILD: Safety and efficacy of naloxegol have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) 12.5 to 25 mg orally once daily. Tablets should be ingested whole and not crushed or chewed (Prod Info MOVANTIK(TM) oral tablets, 2014)
    7.2.2) PEDIATRIC
    A) Safety and efficacy of naloxegol have not been established in pediatric patients (Prod Info MOVANTIK(TM) oral tablets, 2014).

Maximum Tolerated Exposure

    A) In one study, gastrointestinal adverse effects (eg, abdominal pain, diarrhea, and nausea) developed in patients with opioid-induced constipation within 1 to 2 days of using naloxegol 50 mg daily (twice the recommended dosage) (Prod Info MOVANTIK(TM) oral tablets, 2014).
    B) In a randomized, double-blind, 4-way cross-over thorough QTc prolongation study, 150 mg of oral naloxegol (6 times the recommended dosage) resulted in no prolongation of cardiac intervals. No other adverse results were described (Prod Info MOVANTIK(TM) oral tablets, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Naloxegol is a mu-opioid receptor antagonist derivative of naloxone that is specific to peripheral tissues (eg, gastrointestinal tract) due to pegylation that decreases passive permeability and CNS penetration at recommended dosages (Prod Info MOVANTIK(TM) oral tablets, 2014).

Physicochemical

Physical Characteristics

    A) A white to off-white powder, with high aqueous solubility across the physiologic pH range (Prod Info MOVANTIK(TM) oral tablets, 2014).

Molecular Weight

    A) 742 (Prod Info MOVANTIK(TM) oral tablets, 2014)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Bui K, She F, & Sostek M: The effects of renal impairment on the pharmacokinetics, safety, and tolerability of naloxegol. J Clin Pharmacol 2014; Epub:Epub.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    8) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    9) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    10) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    11) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    12) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    13) Product Information: MOVANTIK(TM) oral tablets, naloxegol oral tablets. AstraZeneca (per manufacturer), Wilmington, DE, 2014.
    14) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    15) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    16) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    17) Webster L, Chey WD, Tack J, et al: Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation. Aliment Pharmacol Ther 2014; 40(7):771-779.