Relistor (methylnaltrexone bromide)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Methylnaltrexone bromide is a peripherally acting micro-opiate receptor antagonist.
Methylnaltrexone bromide is a peripherally acting micro-opiate receptor antagonist. The drug is a quaternary amine derivative of the micro-receptor antagonist naltrexone.
Opiates slow intestinal motility and increase GI transit time. The mechanism of action of methylnaltrexone in the management of opiate-induced constipation stems from the drug's ability to block micro-opiate receptors in the GI tract, blocking the intestinal smooth muscle relaxation caused by opiates and thereby reversing opiate-induced slowing of GI transit time. The drug does not readily cross the blood-brain barrier and therefore does not affect opiate analgesic activity or precipitate opiate withdrawal, as is observed with centrally active opiate antagonists (e.g., naltrexone, naloxone).
Methylnaltrexone exhibits greater affinity for micro-opiate receptors than for kappa-opiate receptors; the drug does not interact with delta-opiate receptors nor does it substantially bind to nonopiate receptors. Methylnaltrexone has 2-4% of the opiate antagonist activity and potency of naloxone. Methylnaltrexone appears to possess some micro-receptor agonist activity.
In vitro studies have identified some differences in how methylnaltrexone and alvimopan (both peripheral micro-receptor antagonists) interact with opiate receptors (e.g., differences in binding affinity and functional activity) (see Description in Alvimopan 56:92); however, it remains to be determined whether these differences are clinically important.
Following subcutaneous injection or oral administration of methylnaltrexone bromide, peak plasma concentrations and area under the concentration-time curve (AUC) of the drug increase in a dose-proportional manner over oral and subcutaneous dose ranges of 150-450 mg and 0.15-0.5 mg/kg, respectively. No substantial accumulation of the drug occurs following repeated subcutaneous (12 mg once daily) or oral (450 mg once daily) administration. Peak plasma concentrations are achieved within approximately 0.5 or 1.5 hours following subcutaneous or oral administration, respectively.
The absolute bioavailability of methylnaltrexone bromide tablets has not been established. Administration of a single 450-mg oral dose of the drug with a high-fat meal (approximately 800-1000 calories, with 60% of calories from fat) decreased peak plasma concentration and AUC by 60 and 43%, respectively, and delayed the time to peak plasma concentration by 2 hours. The drug is 11-15% bound to plasma proteins.
Following oral administration of a single 450-mg dose of methylnaltrexone bromide, concentrations of the drug decline in a multiphasic manner with a terminal half-life of approximately 15 hours.
The primary metabolic pathways of methylnaltrexone involve metabolism by aldo-keto reductase 1C enzymes to form methyl-6-naltrexol isomers and conjugation by sulfotransferase (SULT) 1E1 and 2A1 to form methylnaltrexone sulfate; the drug is not appreciably demethylated to form naltrexone. Methylnaltrexone does not undergo first-pass hepatic metabolism following subcutaneous administration, and systemic exposure to methylnaltrexone metabolites is greater following oral administration of a single 450-mg dose than following subcutaneous injection of a single 12-mg dose. The mean steady-state ratio of metabolite AUC to methylnaltrexone AUC was 30, 19, or 9% for methylnaltrexone sulfate, methyl-6alpha-naltrexol, or methyl-6beta-naltrexol, respectively, following subcutaneous administration of 12 mg once daily and 79, 38, or 21%, respectively, following oral administration of 450 mg once daily.
Methylnaltrexone sulfate is a weak micro-opiate receptor antagonist; methyl-6alpha-naltrexol and methyl-6beta-naltrexol are active micro-opiate receptor antagonists.
Following IV administration of radiolabeled methylnaltrexone bromide, approximately 44% of the administered radioactivity was recovered in urine over 24 hours; several metabolites were detected, none of which was recovered in urine in amounts exceeding 6% of the administered radioactivity. After 7 days, 71% of administered radioactivity was recovered (54% in urine and 17% in feces). Following oral administration of methylnaltrexone bromide 450 mg once daily, approximately 1% of the administered dose was recovered in urine as unchanged drug on both day 1 and day 7.
Methylnaltrexone appears to undergo active renal secretion.
USES: This medication is used to treat constipation caused by opioid medication. It blocks the effect of opioids on the gut without blocking the effect on pain. Methylnaltrexone belongs to a class of medications known as opioid antagonists.
Generic name: methylnaltrexone bromide
Pronunciation: (METH-il-nal-TREX-one)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Relistor
Indications
The following indications are listed for Relistor:
- Opioid-Induced Constipation
Dosing
No dosing information is available for this tab.
For the management of opiate-induced constipation, methylnaltrexone bromide is administered orally or by subcutaneous injection in patients with chronic non-cancer-related pain and by subcutaneous injection in those with advanced illness. Patients should be in close proximity to toilet facilities following administration of the drug.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Methylnaltrexone does not substantially inhibit or induce cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, or 3A4 in vitro. In addition, methylnaltrexone does not induce CYP2E1 in vitro. Major metabolites of methylnaltrexone (i.e., methylnaltrexone sulfate, methyl-6alpha-naltrexol, methyl-6beta-naltrexol) do not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor do they induce CYP isoenzymes 1A2, 2B6, or 3A4 in vitro.
Results of in vitro studies indicate that methylnaltrexone and its major metabolites are not likely to cause clinically important interactions via inhibition of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transport protein (OATP) 1B1 or 1B3, organic cation transporter (OCT) 1 or 2, organic anion transporter (OAT) 1 or 3, or multidrug and toxin extrusion transporter (MATE) 1 or 2K at methylnaltrexone bromide dosages of 450 mg orally or 12 mg subcutaneously once daily.
Methylnaltrexone, methyl-6alpha-naltrexol, and methyl-6beta-naltrexol are substrates of OCT1, OCT2, MATE1, and MATE2K in vitro. Methyl-6alpha-naltrexol also is a substrate of BCRP, and methylnaltrexone sulfate is a substrate of MATE2K and a potential substrate of BCRP. Neither methylnaltrexone nor methyl-6beta-naltrexol is a substrate of BCRP. In addition, methylnaltrexone sulfate is not a substrate of OCT1, OCT2, or MATE1. Neither methylnaltrexone nor its 3 major metabolites are substrates of P-gp, MRP2, OATP1B1, OATP1B3, OAT1, or OAT3.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
Because of the potential for GI perforation, methylnaltrexone is contraindicated in patients with known or suspected GI obstruction and in patients at increased risk for recurrent GI obstruction (see GI Perforation under Cautions: Warnings/Precautions).
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in 5% or more of patients with opiate-induced constipation and advanced illness receiving methylnaltrexone bromide injection, and at an incidence at least twice that reported with placebo, include transient abdominal pain, flatulence, nausea, dizziness, and diarrhea.
Adverse effects reported in 2% or more of patients with opiate-induced constipation and chronic non-cancer-related pain receiving oral methylnaltrexone, and at an incidence greater than that reported with placebo, include abdominal pain, diarrhea, headache, abdominal distention, vomiting, hyperhidrosis, anxiety, muscle spasms, rhinorrhea, and chills.
Adverse effects reported in 1% or more of patients with opiate-induced constipation and chronic non-cancer-related pain receiving methylnaltrexone injection, and at an incidence greater than that reported with placebo, include abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and efficacy of methylnaltrexone have not been established in children younger than 18 years of age.
Seizures, tremors, and labored breathing were observed in juvenile rats receiving IV methylnaltrexone for 13 weeks, and the juvenile animals exhibited greater sensitivity to adverse effects of the drug compared with adult animals. The toxicity profile in juvenile dogs was similar to that in adult dogs.
Because of the immature fetal blood-brain barrier, use of methylnaltrexone during pregnancy may precipitate opiate withdrawal in the fetus. Limited available data regarding use of the drug in pregnant women are insufficient to inform a drug-associated risk of major birth defects and spontaneous abortion. No adverse effects of the drug on embryofetal development have been observed in animal reproduction studies. Pregnant women should be advised of potential fetal risk.
It is unknown whether methylnaltrexone is distributed into human milk, affects milk production, or affects nursing infants. Methylnaltrexone is distributed into milk in rats; the drug is detected in milk within 30 minutes after a single subcutaneous injection and is concentrated in milk (up to 24 times plasma concentrations) at 8 hours after administration. Because of the potential for serious adverse effects, including opiate withdrawal, in nursing infants, women should not breast-feed while receiving the drug.
In clinical studies evaluating oral methylnaltrexone, 10% of patients were 65 years of age and older, while 2% were 75 years of age and older. In clinical studies evaluating methylnaltrexone injection, 28% of patients were 65 years of age and older, while 13% were 75 years of age and older. No overall differences in efficacy were observed in these studies between geriatric patients and younger adults. Although adverse effects were similar in geriatric patients and younger adults, a higher incidence of diarrhea was reported in geriatric patients receiving oral methylnaltrexone. Following IV administration of a single 24-mg dose of methylnaltrexone bromide in healthy individuals, clearance of the drug was decreased by approximately 20% and systemic exposure (area under the plasma concentration-time curve (AUC)) was increased by 26% in geriatric adults compared with younger adults. Based on these clinical and pharmacokinetic findings, geriatric patients should be monitored for adverse effects while receiving methylnaltrexone therapy, but dosage adjustments based on age are not necessary.
ICD codes
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Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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