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Methylnaltrexone

Pronunciation

(meth il nal TREKS one)

Index Terms

  • Methylnaltrexone Bromide
  • N-methylnaltrexone Bromide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Kit, Subcutaneous:

Relistor: 12 mg/0.6 mL [contains edetate calcium disodium]

Solution, Subcutaneous:

Relistor: 8 mg/0.4 mL (0.4 mL); 12 mg/0.6 mL (0.6 mL) [contains edetate calcium disodium]

Tablet, Oral, as bromide:

Relistor: 150 mg [contains edetate calcium disodium]

Brand Names: U.S.

  • Relistor

Pharmacologic Category

  • Gastrointestinal Agent, Miscellaneous
  • Opioid Antagonist, Peripherally-Acting

Pharmacology

An opioid receptor antagonist which blocks opioid binding at the mu receptor, methylnaltrexone is a quaternary derivative of naltrexone with restricted ability to cross the blood-brain barrier. It therefore functions as a peripheral acting opioid antagonist, including actions on the gastrointestinal tract to inhibit opioid-induced decreased gastrointestinal motility and delay in gastrointestinal transit time, thereby decreasing opioid-induced constipation. Does not affect opioid analgesic effects.

Distribution

Vdss: ~1.1 L/kg

Metabolism

Metabolized to methyl-6-naltrexol isomers, methylnaltrexone sulfate, and other minor metabolites

Excretion

Urine (~44% to 54%, primarily as unchanged drug); feces (~17%, primarily as unchanged drug)

Time to Peak

SubQ: 30 minutes; Oral: ~1.5 hours (delayed by 2 hours with high fat meal)

Half-Life Elimination

Terminal: ~15 hours (oral)

Protein Binding

11% to 15%

Special Populations: Renal Function Impairment

A single SubQ dose in patients with varying degrees of renal impairment resulted in a 1.3- to 1.9-fold higher AUC0-∞ of methylnaltrexone.

Special Populations: Hepatic Function Impairment

A single oral dose in patients with mild, moderate, and severe hepatic impairment resulted in a 1.7-, 4.8-and 3.8-fold higher Cmax of methylnaltrexone, respectively. AUC0-∞, increased ~2.1-fold in moderate and severe hepatic impairment.

Special Populations: Elderly

In elderly subjects (mean age 72 years old), mean clearance was about 20% lower (56 L/h versus 70 L/h) and AUC was 26% higher.

Use: Labeled Indications

Opioid-induced constipation with advanced illness (injection only): Treatment of opioid-induced constipation in adults with advanced illness (receiving palliative care) who have an inadequate response to conventional laxative regimens.

Opioid-induced constipation with chronic non-cancer pain (tablets and injection): Treatment of opioid-induced constipation in adults with chronic non-cancer pain.

Contraindications

Known or suspected gastrointestinal obstruction; patients at increased risk of recurrent GI obstruction.

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to methylnaltrexone or any component of the formulation

Dosing: Adult

Opioid-induced constipation with chronic non-cancer pain: Note: Discontinue all maintenance laxatives prior to initiation of therapy; if response is not optimal after 3 days, laxative therapy may be reinitiated.

Oral: 450 mg once daily

SubQ: 12 mg once daily

Opioid-induced constipation with advanced illness: SubQ: Dosing is according to body weight: Administer 1 dose every other day as needed; maximum: 1 dose/24 hours

<38 kg: 0.15 mg/kg (round dose up to nearest 0.1 mL of volume)

38 to <62 kg: 8 mg

62 to 114 kg: 12 mg

>114 kg: 0.15 mg/kg (round dose up to nearest 0.1 mL of volume)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥60 mL/minute: No dosage adjustment necessary.

CrCl <60 mL/minute:

Opioid-induced constipation with advanced illness: SubQ:

<38 kg: 0.075 mg/kg every other day (round dose up to nearest 0.1 mL of volume)

38 to <62 kg: 4 mg every other day

62 to 114 kg: 6 mg every other day

>114 kg: 0.075 mg/kg every other day (round dose up to nearest 0.1 mL of volume)

Opioid-induced constipation with chronic non-cancer pain:

Oral: 150 mg once daily

SubQ: 6 mg once daily

End-stage renal impairment (dialysis-dependent): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Opioid-induced constipation with advanced illness: There are no dosage adjustments provided in the manufacturer's labeling. For the injection, consider following the subcutaneous dosing recommendations for opioid-induced constipation with chronic non-cancer pain in patients with severe impairment (Child-Pugh class C).

Opioid-induced constipation with chronic non-cancer pain:

Oral:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe impairment (Child-Pugh class B and C): 150 mg once daily

SubQ:

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child Pugh class C):

<38 kg: 0.075 mg/kg once daily (round dose up to nearest 0.1 mL of volume)

38 to <62 kg: 4 mg once daily

62 to 114 kg: 6 mg once daily

>114 kg: 0.075 mg/kg once daily (round dose up to nearest 0.1 mL of volume)

Administration

Injection: Administer by subcutaneous injection into the upper arm, abdomen, or thigh. Rotate injection sites with each dose.

Tablet: Oral: Administer with water on an empty stomach at least 30 minutes before the first meal of the day.

Storage

Injection: Store intact vials and prefilled syringes between 20°C and 25°C (68°F and 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze. Protect from light. Solution withdrawn from the single use vial is stable in a syringe for 24 hours at room temperature. Do not remove the prefilled syringe from the tray until ready to administer.

Tablets: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Opioid Antagonists: Methylnaltrexone may enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Adverse Reactions

>10%: Gastrointestinal: Abdominal pain (14% to 29%), flatulence (13%), nausea (9% to 12%)

1% to 10%:

Central nervous system: Dizziness (7%), headache (4%), anxiety (2%), chills (1%)

Dermatologic: Hyperhidrosis (3% to 6%)

Endocrine & metabolic: Hot flash (3%)

Gastrointestinal: Diarrhea (5% to 6%), abdominal distention (4%), vomiting (2%)

Neuromuscular & skeletal: Muscle spasm (2%), tremor (1%)

Respiratory: Rhinorrhea (2%)

<1% (Limited to important or life-threatening): Abdominal cramps, diaphoresis, flushing, gastrointestinal perforation, increased body temperature (Thomas 2008), malaise, opioid withdrawal syndrome, pain, syncope (Portenoy 2008)

Warnings/Precautions

Concerns related to adverse effects:

• Diarrhea: Discontinue treatment for severe or persistent diarrhea.

• Gastrointestinal perforation: Gastrointestinal perforations have been reported in patients with advanced illnesses associated with impaired structural integrity of the GI wall (eg, Ogilvie’s syndrome, peptic ulcer disease, diverticular disease, infiltrative GI tract malignancies, or peritoneal metastases). Use with caution in these patients or in patients with other conditions that may result in impaired integrity of the GI wall (eg, Crohn disease); Monitor for development of severe, persistent or worsening abdominal pain; discontinue therapy if this occurs. Use is contraindicated in patients with known or suspected GI obstruction or in patients at increased risk of recurrent GI obstruction.

• Opioid withdrawal: May precipitate symptoms of opioid withdrawal (eg, abdominal pain, anxiety, chills, diarrhea, hyperhidrosis, and yawning). Use with caution in patients with disruptions to the blood-brain barrier; may increase the risk for withdrawal and/or reduced analgesia. Monitor for symptoms of opioid withdrawal in such patients.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustments recommended for moderate to severe hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended for moderate to severe renal impairment (CrCl <60 mL/minute).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Use of injection beyond 4 months has not been studied. Discontinue methylnaltrexone if opioids are discontinued.

• Opioid-induced constipation with chronic non-cancer pain: Appropriate use: Efficacy has been established in patients who have taken opioids for ≥4 weeks; sustained exposure to opioids prior to initiation of methylnaltrexone may increase sensitivity to effects. All laxative maintenance therapy should be discontinued prior to initiation of therapy; laxative therapy may be added if a suboptimal response to therapy is noted after 3 days. When the opioid regimen has been changed, the patient should be re-evaluated for the need to continue methylnaltrexone therapy.

Monitoring Parameters

Severe, persistent, or worsening abdominal pain; symptoms of opioid withdrawal; adequate analgesia.

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Maternal use of methylnaltrexone during pregnancy may precipitate opioid withdrawal effects in newborn.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

Patient may experience sensation of fullness, headache, muscle spasm, rhinorrhea, dizziness, flushing, or flatulence. Have patient report immediately to prescriber severe diarrhea; persistent diarrhea; chills; severe abdominal pain; severe abdominal edema; tremors; vomiting blood; nausea; vomiting; or black, tarry, or bloody stools (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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