Relistor

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• dizziness, lightheadedness, and fainting when you get up too quickly from a lying position
• chills
• sweating
• runny nose
• diarrhea
• abdominal pain
• anxiety
• yawning
• decrease in the pain relieving effects of the opioid medication

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Take Relistor exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The Relistor dose your doctor recommends will be based on the following:

• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your liver function
• your weight

The recommended dose of Relistor tablets is 450 mg once daily. 

The recommended dose of Relistor is 8 mg subcutaneously for opioid-induced constipation and advanced illness adult patients weighing 38 kg to less than 62 kg or 12 mg subcutaneously for patients weighing 62 kg to 114 kg. 

Adult patients whose weight falls outside of these ranges should be dosed at 0.15 mg/kg.

Peripherally acting μ-opiate receptor antagonist;1 2 3 4 7 8 9 12 13 quaternary amine derivative of naltrexone.4 7 9 11 13

Absorption

Bioavailability

Rapidly absorbed following sub-Q administration.1

Onset

Laxation within 30 minutes in about 30% of patients; within 4 hours in about 50–60% of patients.1

Distribution

Extent

Moderate tissue distribution.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

11–15%.1 13

Elimination

Metabolism

Metabolized to several minor metabolites.1 Not appreciably demethylated to form naltrexone.1 4 13

Elimination Route

Excreted principally as unchanged drug in urine (50%) and in feces.1 13

Half-life

Approximately 8 hours.1

Special Populations

Mild or moderate hepatic impairment does not affect systemic exposure; not studied in patients with severe hepatic impairment.1 10

Severe renal impairment (Clcr <30 mL/minute) decreases renal clearance 8- to 9-fold and doubles AUC.1 (See Renal Impairment under Dosage and Administration.)

Not studied in patients with end-stage renal disease requiring dialysis.1 10

• Peripherally acting μ-opiate receptor antagonist;1 7 8 9 12 13 quaternary amine derivative of naltrexone.4 7 9 11 13

• Blocks μ-opiate receptors in the GI tract, blocking intestinal smooth muscle relaxation caused by opiates and thereby reversing opiate-induced slowing of GI transit time.1 2 4

• Does not readily cross blood-brain barrier; therefore, does not affect opiate analgesic activity or precipitate opiate withdrawal, unlike centrally active opiate antagonists (e.g., naltrexone, naloxone).1 2 3 4 5 7 8 9 11 12 13

• Exhibits greater affinity for μ-opiate receptors than for κ-opiate receptors; does not interact with δ-opiate receptors nor substantially bind to nonopiate receptors.9 12 13

• 2–4% of the opiate antagonist activity and potency of naloxone;13 possesses some μ-receptor agonist activity.6 12 13

Methylnaltrexone injection is used to treat constipation caused by opioids (narcotic pain medicines), in adults with long-lasting pain that is not caused by cancer or adults with advanced illness. This medicine is used when other medicines for constipation (laxatives) have not worked well.

This medicine is available only with your doctor's prescription.

 Other Opioid Antagonists

Avoid concomitant use of Relistor with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

Drugs Metabolized by Cytochrome P450 Isozymes

In healthy subjects, a subcutaneous dose of 0.3 mg/kg of Relistor did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

Pregnancy

Risk Summary

The limited available data with Relistor in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriages. There are clinical considerations when Relistor is used by pregnant women [see Clinical Considerations]. In animal reproduction studies, no effects on embryofetal development were observed with the administration of intravenous methylnaltrexone bromide during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the subcutaneous maximum recommended human dose (MRHD) of 12 mg Relistor injection per day. The intravenous doses in rats and rabbits are about 0.5 times and 0.7 times, respectively, the oral MRHD of 450 mg/day [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

The use of Relistor during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier.

Data

Animal Data

Reproduction studies have been performed with methylnaltrexone bromide administered during the period of organogenesis to rats at intravenous doses up to 25 mg/kg/day (about 20 times the subcutaneous MRHD of 12 mg/day based on body surface area), and did not cause any adverse effects on embryofetal development. In rabbits, intravenous doses of methylnaltrexone bromide up to 16 mg/kg/day (about 26 times the subcutaneous MRHD of 12 mg/day) did not show any embryofetal toxicity. The intravenous doses in rats (25 mg/kg/day) and rabbits (16 mg/kg/day) are about 0.5 and 0.7 times, respectively, the oral MRHD of 450 mg/day based on body surface area. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses of methylnaltrexone bromide up to 100 mg/kg/day (about 81 times the subcutaneous MRHD of 12 mg/day; about 2.2 times the oral MRHD of 450 mg/day).

Lactation

Risk Summary

There is no information regarding the presence of methylnaltrexone in human milk, the effects on the breastfed infant, or the effects on milk production. Methylnaltrexone is present in rat milk [see Data]. Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with Relistor.

Data

Radioactivity appeared in rat milk within 30 minutes of a single subcutaneous administration of radiolabeled methylnaltrexone bromide and was concentrated up to 24-fold at 8 hours after administration relative to plasma concentrations.

Pediatric Use

Safety and effectiveness of Relistor tablets and injection have not been established in pediatric patients.

Juvenile Animal Studies

In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions, tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone when compared to adult animals. Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs [see Nonclinical Toxicology (13.2)].

Geriatric Use

Of the total number of patients in clinical studies of Relistor tablets, a total of 136 patients (10%) were aged 65 years and older, while 23 (2%) were aged 75 and older. In clinical studies of Relistor tablets, no overall differences in effectiveness were observed. Adverse reactions were similar; however, there was a higher incidence of diarrhea in elderly patients.

Of the total number of patients in clinical studies of Relistor injection, a total of 226 (28%) were aged 65 years and older, while 108 (13%) were aged 75 years and older. In clinical studies of Relistor injection, no overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dosage adjustment based on age is recommended. Monitor elderly patients for adverse reactions.

Renal Impairment

In a study of subjects with varying degrees of renal impairment receiving Relistor injection subcutaneously, there was a significant increase in the exposure to methylnaltrexone in subjects with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault) compared to healthy subjects [see Clinical Pharmacology (12.3)].

Therefore, a dosage reduction of Relistor tablets and Relistor injection is recommended in patients with moderate and severe renal impairment [see Dosage and Administration (2.4)]. No dosage adjustment of Relistor tablets or Relistor injection is needed in patients with mild renal impairment (creatinine clearance greater than 60 mL/minute as estimated by Cockcroft-Gault).

Hepatic Impairment

Tablets

In a study of subjects with varying degrees of hepatic impairment receiving a 450 mg dose of Relistor tablets, there was a significant increase in systemic exposure of methylnaltrexone for subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, a dosage reduction of Relistor tablets is recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.5)]. No dosage adjustment of Relistor tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A).

Injection

In a study of subjects with mild or moderate hepatic impairment, there was no clinically meaningful change in systemic exposure of methylnaltrexone compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, no dosage adjustment of Relistor injection is needed for patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)].

Patients with severe hepatic impairment were not studied. In patients with severe hepatic impairment, monitor for methylnaltrexone-related adverse reactions. If considering dosage adjustment, follow the recommendations in Table 3 [see Dosage and Administration (2.5)].

Relistor® (methylnaltrexone bromide) is a mu-opioid receptor antagonist. The chemical name for methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methobromide. The molecular formula is C21H26NO4Br, and the molecular weight is 436.36.

The structural formula is:

Relistor tablets for oral administration are film-coated and contain 150 mg of methylnaltrexone bromide (equivalent to 122.5 mg methylnaltrexone). Inactive ingredients are silicified microcrystalline cellulose, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, crospovidone, poloxamer 407, stearic acid (vegetable source), colloidal silicon dioxide, edetate calcium disodium, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Relistor for subcutaneous administration is a sterile, clear and colorless to pale yellow aqueous solution. Each 3 mL vial contains 12 mg of methylnaltrexone bromide (equivalent to 9.8 mg of methylnaltrexone) in 0.6 mL of water. The excipients are 3.9 mg sodium chloride USP, 0.24 mg edetate calcium disodium USP, and 0.18 mg glycine hydrochloride. During manufacture, the pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.

Each 8 mg/0.4 mL pre-filled syringe (1 mL syringe) contains 8 mg of methylnaltrexone bromide (equivalent to 6.5 mg of methylnaltrexone) in 0.4 mL of water. The excipients are 2.6 mg sodium chloride USP, 0.16 mg edetate calcium disodium USP, and 0.12 mg glycine hydrochloride.

Each 12 mg/0.6 mL pre-filled syringe (1 mL syringe) contains 12 mg of methylnaltrexone bromide (equivalent to 9.8 mg of methylnaltrexone) in 0.6 mL of water. The excipients are 3.9 mg sodium chloride USP, 0.24 mg edetate calcium disodium USP, and 0.18 mg glycine hydrochloride.

More Common Side Effects

The more common side effects that can occur with use of Relistor include: 

• pain in your abdomen

• nausea

• diarrhea

• sweating

• flushing

• tremor

• chills

• dizziness

• gas

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious Side Effects

Call your doctor right away if you have serious side effects. Call 9-1-1 if your symptoms feel life-threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

• Tearing in the wall of your stomach or intestine. Symptoms can include:

  • severe, long-lasting, or worsening pain in your abdomen
  • chills
  • fever
  • nausea
  • vomiting

• Severe diarrhea. Symptoms can include:

  • having more than six bowel movements per day
  • diarrhea that lasts longer than 48 hours

• Opioid withdrawal. Symptoms can include:

  • sweating
  • chills
  • diarrhea
  • pain in your abdomen
  • anxiety
  • yawning

Relistor can interact with other medications, vitamins, or herbs you may be taking. An interaction is when a substance changes the way a drug works. This can be harmful or prevent the drug from working well.

To help avoid interactions, your doctor should manage all of your medications carefully. Be sure to tell your doctor about all medications, vitamins, or herbs you’re taking. To find out how this drug might interact with something else you’re taking, talk to your doctor or pharmacist.

Medications that might interact with this drug

Do not take these drugs with Relistor. Doing so can cause dangerous effects in the body. Examples of these drugs include:

• Opioid antagonists, such as naltrexone, naloxone, buprenorphine, or buprenorphine/naloxone
  • Taking these drugs with Relistor raises your risk of symptoms of opioid withdrawal. These symptoms include sweating, chills, diarrhea, or pain in your abdomen.

People with current or past bowel blockage

If you have bowel blockage (intestinal obstruction) or have had it in the past, this drug raises your risk of tearing the wall of your stomach or intestine. The tear may cause bowel blockage to occur again.

People with kidney disease

Your body processes this drug more slowly if you have serious kidney disease. Your doctor will likely prescribe you half of the recommended dose. Be sure to use the pre-filled syringe. It will help you make sure your dose is correct.

Pregnant women

This drug is a category C pregnancy drug. That means two things:

1. Research in animals has shown adverse effects to the fetus when the mother takes the drug.
2. There haven’t been enough studies done in humans to be certain how the drug might affect the fetus.

Talk to your doctor if you’re pregnant or planning to become pregnant. This drug should only be used if the potential benefit justifies the potential risk to the unborn baby. 

Using this drug while pregnant could cause opioid withdrawal in your baby. If this occurs, your baby’s symptoms could appear as soon as one day after birth and last up to six months. Your doctor might treat your baby to reduce your baby’s withdrawal symptoms.

Women who are breast-feeding

It’s not known whether this drug passes into human breast milk. If it does, it could cause serious side effects in a child who is breastfed. These side effects include opioid withdrawal. 

To avoid these side effects, you should either stop breastfeeding or stop taking this drug. Talk with your doctor about which option is best for you.

For seniors

The kidneys of older adults may not work as well as they used to. This can cause your body to process drugs more slowly. As a result, more of a drug stays in your body for a longer time. This raises your risk of side effects.

For children

This drug has not been studied in children. It should not be used in people younger than 18 years.

When to call the doctor

Call your doctor right away if you become pregnant while taking this drug.

Allergies

This drug can cause a severe allergic reaction. Symptoms can include: 

• trouble breathing
• swelling of your throat or tongue 

If you have an allergic reaction, call your doctor or local poison control center right away. If your symptoms are severe, call 9-1-1 or go to the nearest emergency room.

Taking this drug again if you’ve ever had an allergic reaction to it could be fatal (cause death). Be sure to tell your doctor if you’ve ever had an allergic reaction to this drug.