Drugs Details

Drugs Info of Relistor
Drugs Details
  • Drugs Type  : FDA
  • Date : 19th Mar 2015 04:36 am
  • Brand Name : Relistor
  • Generic Name : methylnaltrexone (Pronunciation: METh IL nal TREX own)
Descriptions

RELISTOR (methylnaltrexone bromide) injection, a mu-opioid receptor antagonist, is a sterile, clear and colorless to pale yellow aqueous solution. The chemical name for methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methobromide. The molecular formula is C21H26NO4Br, and the molecular weight is 436.36.

Each 3 mL vial contains 12 mg of methylnaltrexone bromide 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 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 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.

The structural formula is:

 

RELISTOR (methylnaltrexone bromide) Structural Formula Illustration

What are the possible side effects of methylnaltrexone (Relistor)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have severe or ongoing diarrhea, stomach pain that will not go away, black or bloody stools, coughing up blood, or nausea or vomiting that are new or worsening symptoms.

Less serious side effects may include:

  • stomach pain, gas;
  • mild nausea or diarrhea;
  • dizziness; or
  • increased sweating.

This is not a complete list of side effects and...

Read All Potential Side Effects and See Pictures of Relistor »

This monograph has been modified to include the generic and brand name in many instances.

Indications

Opioid-Induced Constipation In Adult Patients With Chronic Non-Cancer Pain

RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

Opioid-Induced Constipation In Adult Patients With Advanced Illness

RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

Limitation of Use

Use of RELISTOR beyond four months has not been studied in the advanced illness population.

Dosage Administration

Important Administration Information

  • RELISTOR is for subcutaneous use only.
  • Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).
  • Be within close proximity to toilet facilities once RELISTOR is administered.
  • Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued.
  • In patients with chronic non-cancer pain and opioid-induced constipation:
    • RELISTOR has been shown to be efficacious in patients who have taken opioids for at least 4 weeks. Sustained exposure to opioids prior to starting RELISTOR may increase the patient's sensitivity to the effects of RELISTOR [see Clinical Studies].
    • Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days.
    • Inject one dose every day.
    • Re-evaluate the continued need for RELISTOR when the opioid regimen is changed to avoid adverse reactions.
  • In patients with advanced illness and opioid-induced constipation:
    • Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.

Opioid-Induced Constipation In Adult Patients With Chronic Non-Cancer Pain

The recommended dosage of RELISTOR is 12 mg subcutaneously once daily [see Clinical Studies].

Opioid-Induced Constipation In Adult Patients With Advanced Illness

The recommended dose of RELISTOR administered subcutaneously is 8 mg for adult patients weighing 38 kg to less than 62 kg and 12 mg 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. The recommended dosage regimen is one dose every other day, as needed [see Clinical Studies].

See Table 1 to determine the correct dose by patient weight and injection volume to be administered. The pre-filled syringe is designed to deliver a fixed dose; therefore, adult patients requiring dosing calculated on a mg/kg basis should not be prescribed pre-filled syringes.

Table 1: Weight-Based Dosing of RELISTOR and Corresponding Injection Volume for Adult Patients with Opioid-Induced Constipation and Advanced Illness

Weight of Adult Patient Subcutaneous Dose Injection Volume
Less than 38 kg 0.15 mg/kg See below*
38 kg to less than 62 kg 8 mg 0.4 mL
62 kg to 114 kg 12 mg 0.6 mL
More than 114 kg 0.15 mg/kg See below*
*The injection volume for these patients should be calculated using the following method:

Multiply the patient weight in kilograms by 0.0075 and round up the volume to the nearest 0.1 mL.

Use in Patients With Severe Renal Impairment

In adult patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault), dose reduction of RELISTOR by one-half is recommended [see Use in Specific Populations]. No dosage adjustment is recommended for adult patients with mild to moderate renal impairment.

The pre-filled syringe is designed to deliver a fixed dose; therefore, adult patients with severe renal impairment should only be prescribed single-use vials to ensure correct dosing.

Administration And Storage

RELISTOR is a sterile, clear, and colorless to pale yellow aqueous solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the vial if any of these are present.

Single-use Vials

Once drawn into the 1 mL syringe with a 27-gauge x ½-inch needle, if immediate administration is not possible, store at ambient room temperature and administer within 24 hours. Discard any unused portion that remains in the vial. Advise patients concerning proper training in subcutaneous technique.

Single-use Pre-filled Syringes

Only adult patients requiring an 8 mg or 12 mg dose should be prescribed pre-filled syringes. Do not remove the pre-filled syringe from the tray until ready to administer.

How Supplied

Dosage Forms And Strengths

Single-use Vial
  • 12 mg/0.6 mL solution for subcutaneous injection, for use with a 27 gauge x ½- inch needle and 1 mL syringe
  • 12 mg/0.6 mL solution for subcutaneous injection, with one 1 mL syringe with retractable 27 gauge x ½-inch needle, two alcohol swabs
Single-use Pre-filled Syringe
  • 8 mg/0.4 mL solution for subcutaneous injection, with a 29-gauge x ½-inch fixed needle and a needle guard
  • 12 mg/0.6 mL solution for subcutaneous injection, with a 29-gauge x ½-inch fixed needle and a needle guard

Storage And Handling

 

NDC NUMBER PACK SIZE CONTENTS
65649-551-02 1 vial per carton one 12 mg/0.6 mL single-use vial
65649-553-05 7 trays per kit Each tray contains: one 12 mg/0.6 mL single-use vial, one 1 cc (mL) syringe with retractable (27-gauge x '/-inch) needle (VanishPoint®), two alcohol swabs
65649-552-04 7 pre-filled syringes per carton seven 8 mg/0.4 mL single-use pre-filled syringes with needle guard system
65649-551-03 7 pre-filled syringes per carton seven 12 mg/0.6 mL single-use pre-filled syringes with needle guard system
65649-551-07 1 pre-filled syringe per carton one 12mg/0.6 mL single-use pre-filled syringe with needle guard system
Storage

RELISTOR should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not freeze.

Protect from light.

Manufactured for: Salix Pharmaceuticals, Inc., Raleigh, NC 27615. Under license from: Progenics Pharmaceuticals, Inc., Tarrytown, NY 10591. Revised: September 2014

This monograph has been modified to include the generic and brand name in many instances.

Side Effects

Serious and important adverse reactions described elsewhere in labeling include:

  • Gastrointestinal perforation [see WARNINGS AND PRECAUTIONS]
  • Severe or persistent diarrhea [see WARNINGS AND PRECAUTIONS]
  • Opioid withdrawal [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain

The safety of RELISTOR was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 4-week, double-blind, placebocontrolled period in which adult patients were randomized to receive RELISTOR 12 mg once daily (150 patients) or placebo (162 patients) [see Clinical Studies]. After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily.

Adverse reactions in adult patients with opioid-induced constipation and chronic noncancer pain receiving RELISTOR are shown in Table 2. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

Table 2: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR in Adult Patients with Opioid-Induced Constipation and Chronic Non-Cancer Pain

Adverse Reaction RELISTOR 12 mg once daily
n = 150
Placebo
n = 162
Abdominal Pain 21% 6%
Nausea 9% 6%
Diarrhea 6% 4%
Hyperhidrosis 6% 1%
Hot Flush 3% 2%
Tremor 1% < 1%
Chills 1% 0%
* Adverse reactions occurring in ≥ 1 % of patients receiving RELISTOR 12 mg once daily and at an incidence greater than placebo.

During the 4-week double-blind period, in patients with opioid-induced constipation and chronic non-cancer pain that received RELISTOR 12 mg every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature change (3%), piloerection (3%), and chills (2%) as compared to daily Relistor dosing. Use of RELISTOR 12 mg every other day is not recommended in patients with OIC and chronic non-cancer pain [see DOSAGE AND ADMINISTRATION]. The rates of discontinuation due to adverse reactions during the double-blind period (Study 1) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%).

The safety of RELISTOR was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 2). Patients were allowed to administer RELISTOR 12 mg less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4-week double-blind period of Study 1. Additionally, in Study 2, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR.

Opioid-Induced Constipation in Adult Patients with Advanced Illness

The safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in adult patients with opioid-induced constipation and advanced illness receiving palliative care: Study 3 included a single-dose, double-blind, placebo-controlled period, whereas Study 4 included a 14-day multiple dose, double-blind, placebo-controlled period [see Clinical Studies].

The most common ( ≥ 5%) adverse reactions in adult patients with opioid-induced constipation and advanced illness receiving RELISTOR are shown in Table 3 below.

Table 3: Adverse Reactions from all Doses in Double-Blind, Placebo-Controlled Clinical Studies of RELISTOR in Adult Patients with Opioid-Induced Constipation and Advanced Illness*

Adverse Reaction RELISTOR
n = 165
Placebo
n = 123
Abdominal Pain 29% 10%
Flatulence 13% 6%
Nausea 12% 5%
Dizziness 7% 2%
Diarrhea 6% 2%
* Adverse reactions occurring in ≥ 5 % of patients receiving all doses of RELISTOR (0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo.

The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1%) and placebo (2%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of RELISTOR. Because they are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal

Perforation, cramping, vomiting

General Disorders and Administrative Site Disorders

Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported [see WARNINGS AND PRECAUTIONS].

Read the Relistor (methylnaltrexone bromide) Side Effects Center for a complete guide to possible side effects

Learn More »

Interactions

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 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

This monograph has been modified to include the generic and brand name in many instances.

Warnings

Included as part of the PRECAUTIONS section.

Precautions

Gastrointestinal Perforation

Cases of gastrointestinal perforation have been reported in adult patients with opioidinduced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie's syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom [see CONTRAINDICATIONS].

Severe Or Persistent Diarrhea

If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider.

Opioid Withdrawal

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR [see ADVERSE REACTIONS]. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients.

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Administration

Advise all patients to:

  • Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).
  • Safely dispose of needles by following the sharps disposal recommendations described in the RELISTOR Instructions for Use.
  • Be within close proximity to toilet facilities once RELISTOR is administered.
  • Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued.

Advise chronic non-cancer pain patients receiving RELISTOR for opioid-induced constipation to:

  • Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days.
  • Inject one dose every day.
  • Inform their healthcare provider if their opioid regimen is changed, to avoid adverse reactions, such as diarrhea.

Advise patients with advanced illness receiving RELISTOR for opioid-induced constipation to:

  • Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.
Gastrointestinal Perforation

Advise patients to discontinue RELISTOR and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain [see WARNINGS AND PRECAUTIONS].

Severe or Persistent Diarrhea

Advise patients to discontinue RELISTOR if they experience severe or persistent diarrhea.

Opioid Withdrawal

Advise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Pregnancy

Advise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.

Nursing

Advise females who are nursing against breastfeeding during treatment with RELISTOR due to the potential for opioid withdrawal in nursing infants.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Two-year oral carcinogenicity studies have been conducted with methylnaltrexone in CD-1 mice at doses up to 200 mg/kg/day (about 81 times the maximum recommended human (MRHD) dose of 0.2 mg/kg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the MRHD of 0.2 mg/kg/day based on body surface area) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the MRHD of 0.2 mg/kg/day based on body surface area). Oral administration of methylnaltrexone for 104 weeks did not produce tumors in mice and rats.

Mutagenesis

Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test.

Impairment of Fertility

Methylnaltrexone bromide at subcutaneous doses up to 150 mg/kg/day (about 122 times the MRHD of 0.2 mg/kg/day based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with RELISTOR in pregnant women. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day. RELISTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Data

Animal Data

Reproduction studies have been performed with methylnaltrexone administered during the period of organogenesis to rats at intravenous doses up to 25 mg/kg/day (about 20 times the MRHD of 0.2 mg/kg/day based on body surface area) and did not cause any adverse effects on embryofetal development. In rabbits, intravenous doses of methylnaltrexone up to 16 mg/kg/day (about 26 times the MRHD of 0.2 mg/kg/day based on body surface area) did not show any embryofetal toxicity. 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 up to 100 mg/kg/day (about 81 times the MRHD of 0.2 mg/kg/day based on body surface area).

Nursing Mothers

It is not known whether RELISTOR is present in human milk.

However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of RELISTOR have not been established in pediatric patients.

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 bromide 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].

Geriatric Use

In the double-blind studies, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended.

Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment. Dose-reduction by one half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault) [see DOSAGE AND ADMINISTRATION].

Hepatic Impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment [see CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

OverDose

During clinical trials of RELISTOR administered subcutaneously, no cases of methylnaltrexone bromide overdose were reported.

A study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate.

If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

ContrainDications

RELISTOR is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation [see WARNINGS AND PRECAUTIONS].

This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

Mechanism of Action

Methylnaltrexone is a selective antagonist of opioid binding at the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is restricted. This allows methylnaltrexone to function as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system.

Pharmacodynamics

Effect on Cardiac Repolarization

In a randomized, double-blind placebo- and (open-label) moxifloxacin-controlled 4-period crossover study, 56 healthy subjects were administered methylnaltrexone bromide 0.3 mg/kg and methylnaltrexone bromide 0.64 mg/kg by intravenous infusion over 20 minutes, placebo, and a single oral dose of moxifloxacin. At both the 0.3 mg/kg and 0.64 mg/kg methylnaltrexone bromide doses, no significant effect on the QTc interval was detected.

Pharmacokinetics

Absorption

Following subcutaneous administration, methylnaltrexone achieved peak concentrations (Cmax) at approximately 0.5 hours. Across the range of doses from 0.15 mg/kg to 0.50 mg/kg, mean Cmax and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner. There was no accumulation of methylnaltrexone following once-daily subcutaneous dosing of methylnaltrexone bromide 12 mg for seven consecutive days in healthy subjects.

Table 3: Pharmacokinetic Parameters of Methylnaltrexone Following Subcutaneous Doses

Parameter 0.15 mg/kg single dose 12 mg single dose 12 mg at steady-state
Cmax (ng/mL)i 117 (32.7) 140 (35.6) 119 (27.2)
tmax (hr)ii 0.5 (0.25-0.75) 0.25 (0.25-0.5) 0.25 (0.25-0.5)
AUC24 (ng·hr/mL) i 175 (36.6) 218 (28.3) 223 (28.2)
i Expressed as mean (SD).
iiExpressed as median (range).
Distribution

The steady-state volume of distribution (Vss) of methylnaltrexone is approximately 1.1 L/kg. The fraction of methylnaltrexone bound to human plasma proteins is 11.0% to 15.3%, as determined by equilibrium dialysis.

Metabolism

In a mass balance study, approximately 44% of the administered radioactivity was recovered in the urine over 24 hours with 5 distinct metabolites and none of the detected metabolites was in amounts over 6% of administered radioactivity. Conversion to methyl-6-naltrexol isomers (5% of total) and methylnaltrexone sulfate (1.3% of total) appear to be the primary pathways of metabolism. N-demethylation of methylnaltrexone to produce naltrexone is not significant.

After 12 mg once daily dosing the mean AUC0-24 ratio of metabolites to methylnaltrexone at steady-state was 30%, 19%, and 9% for methylnaltrexone sulfate, methyl-6α-naltrexol, and methyl-6β-naltrexol, respectively. Methyl-6α-naltrexol, and methyl-6β-naltrexol were active mu-opioid receptor antagonists and methylnaltrexone sulfate is a weak mu-opioid receptor antagonist.

Methylnaltrexone is conjugated by sulfotransferase SULT1E1 and SULT2A1 isoforms to methylnaltrexone sulfate. Conversion to methyl-6-naltrexol isomers is mediated by aldo-keto reductase 1C enzymes.

Excretion

After intravenous administration, approximately half of the dose was excreted in the urine (53.6%) and 17.3% of administered dose was excreted in the feces up to 168 hours postdose. Methylnaltrexone is excreted primarily as the unchanged drug in the urine and feces. The terminal half-life (t½) is approximately 8 hours. Active renal secretion of methylnaltrexone is suggested by renal clearance of methylnaltrexone that is approximately 4-5 fold higher than creatinine clearance.

Specific Populations

Geriatric

A study was conducted to characterize the pharmacokinetics of methylnaltrexone after single dose of 24 mg methylnaltrexone via intravenous infusion over 20 min in healthy adults between 18 and 45 years of age and in healthy adults aged 65 years and older. In elderly subjects, mean clearance was about 20% lower (56 L/h versus 70 L/h) and AUC∞ was 26% higher than in subjects between 18 and 45 years of age.

Renal impairment

In a study of volunteers with varying degrees of renal impairment receiving a single dose of 0.30 mg/kg methylnaltrexone bromide, renal impairment had a marked effect on the renal excretion of methylnaltrexone. Severe renal impairment decreased the renal clearance of methylnaltrexone by 8- to 9-fold and resulted in a 2-fold increase in total methylnaltrexone exposure (AUC). Mean Cmax was not significantly changed.

Hepatic impairment

The effect of mild and moderate hepatic impairment on the systemic exposure to methylnaltrexone has been studied in 8 subjects each, with Child-Pugh Class A and B, compared to healthy subjects. Results showed no meaningful effect of hepatic impairment on the AUC or Cmax of methylnaltrexone.

Drug Interactions

In vitro studies suggested that methylnaltrexone was a substrate of Organic Cation Transporter 1 but not a substrate of Organic Anion Transporter 1 or of P-glycoprotein.

Cimetidine

A clinical drug interaction study in healthy adult subjects evaluated the effects of cimetidine, a drug that inhibits the active renal secretion of organic cations, on the pharmacokinetics of methylnaltrexone (24 mg administered as an IV infusion over 20 minutes). A single dose of methylnaltrexone was administered before cimetidine dosing and with the last dose of cimetidine (400 mg every 8 hours for 6 days). Mean Cmax and AUC of methylnaltrexone increased by 10% with concomitant cimetidine administration. The renal clearance of methylnaltrexone decreased about 40%.

Animal Toxicology and/or Pharmacology

In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone bromide caused concentration-dependent inhibition of hERG current (1%, 12%, 13% and 40% inhibition at 30, 100, 300 and 1000 μM concentrations, respectively). Methylnaltrexone bromide had a hERG IC50 of > 1000 μM. In isolated dog Purkinje fibers, methylnaltrexone bromide caused prolongations in action potential duration (APD). The highest tested concentration (10 μM) in the dog Purkinje fiber study was about 18 and 37 times the Cmax at human subcutaneous (SC) doses of 0.3 and 0.15 mg/kg, respectively. In isolated rabbit Purkinje fibers, methylnaltrexone bromide (up to 100 μM) did not have an effect on APD, compared to vehicle control. The highest methylnaltrexone bromide concentration (100 μM) tested was about 186 and 373 times the human Cmax at SC doses of 0.3 and 0.15 mg/kg, respectively. In anesthetized dogs, methylnaltrexone bromide caused decreases in blood pressure, heart rate, cardiac output, left ventricular pressure, left ventricular end diastolic pressure, and +dP/dt at ≥ 1 mg/kg. In conscious dogs, methylnaltrexone bromide caused a dose-related increase in QTc interval. After a single intravenous dosage of 20 mg/kg to beagle dogs, predicted Cmax and AUC values were approximately 482 and 144 times, respectively, the exposure at human SC dose of 0.15 mg/kg and 241 times and 66 times, respectively, the exposure at a human SC dose of 0.3 mg/kg. In conscious guinea pigs, methylnaltrexone caused mild prolongation of QTc (4% over baseline) at 20 mg/kg, intravenous. A thorough QTc assessment was conducted in humans [see CLINICAL PHARMACOLOGY].

In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions, tremors and labored breathing occurred at dosages of 3 and 10 mg/kg/day (about 3.2 and 11 times, respectively, the recommended human dose of 0.15 mg/kg based on the body surface area). Similar adverse clinical signs were seen in adult rats at 20 mg/kg/day (about 22 times the recommended human dose of 0.15 mg/kg based on the body surface area). Juvenile rats were found to be more sensitive to the toxicity of methylnaltrexone bromide when compared to adults. The no observed adverse effect levels (NOAELs) in juvenile and adult rats were 1 and 5 mg/kg/day, respectively (about 1.1 and 5.4 times respectively, the recommended human dose of 0.15 mg/kg based on the body surface area).

In juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks, juvenile dogs had a toxicity profile similar to adult dogs. Following intravenous administration of methylnaltrexone bromide for 13 weeks, decreased heart rate (13.2 % reduction compared to pre-dose) in juvenile dogs and prolonged QTc interval in juvenile (9.6% compared to control) and adult (up to 15% compared to control) dogs occurred at 20 mg/kg/day (about 72 times the recommended human subcutaneous doses of 0.15 mg/kg based on the body surface area). Clinical signs consistent with effects on the CNS (including tremors and decreased activity) occurred in both juvenile and adult dogs. The NOAELs in juvenile and adult dogs were 5 mg/kg/day (about 18 times the recommended human subcutaneous doses of 0.15 mg/kg based on the body surface area).

Clinical Studies

The efficacy and safety of RELISTOR in the treatment of opioid-induced constipation in advanced illness patients receiving palliative care was demonstrated in two randomized, double-blind, placebo-controlled studies. In these studies, the median age was 68 years (range 21-100); 51% were females. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer's disease/dementia, HIV/AIDS, or other advanced illnesses. Prior to screening, patients had been receiving palliative opioid therapy (median daily baseline oral morphine equivalent dose = 172 mg), and had opioid-induced constipation (either < 3 bowel movements in the preceding week or no bowel movement for > 2 days). Patients were on a stable opioid regimen ≥ 3 days prior to randomization (not including PRN or rescue pain medication) and received their opioid medication during the study as clinically needed. Patients maintained their regular laxative regimen for at least 3 days prior to study entry, and throughout the study. Rescue laxatives were prohibited from 4 hours before to 4 hours after taking an injection of study medication.

Study 1 compared a single, double-blind, subcutaneous dose of RELISTOR 0.15 mg/kg, or RELISTOR 0.3 mg/kg versus placebo. The double-blind dose was followed by an open-label 4-week dosing period, where RELISTOR could be used as needed, no more frequently than 1 dose in a 24 hour period. Throughout both study periods, patients maintained their regular laxative regimen. A total of 154 patients (47 RELISTOR 0.15 mg/kg, 55 RELISTOR 0.3 mg/kg, 52 placebo) were enrolled and treated in the double-blind period. The primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of the double-blind dose of study medication. RELISTOR-treated patients had a significantly higher rate of laxation within 4 hours of the double-blind dose (62% for 0.15 mg/kg and 58% for 0.3 mg/kg) than did placebo-treated patients (14%); p < 0.0001 for each dose versus placebo (Figure 1).

Study 2 compared double-blind, subcutaneous doses of RELISTOR given every other day for 2 weeks versus placebo. Patients received opioid medication ≥ 2 weeks prior to receiving study medication. During the first week (days 1, 3, 5, 7) patients received either 0.15 mg/kg RELISTOR or placebo. In the second week the patient's assigned dose could be increased to 0.30 mg/kg if the patient had 2 or fewer rescue-free laxations up to day 8. At any time, the patient's assigned dose could be reduced based on tolerability. Data from 133 (62 RELISTOR, 71 placebo) patients were analyzed. There were 2 primary endpoints: proportion of patients with a rescue-free laxation within 4 hours of the first dose of study medication and proportion of patients with a rescue-free laxation within 4 hours after at least 2 of the first 4 doses of study medication. RELISTOR-treated patients had a higher rate of laxation within 4 hours of the first dose (48%) than placebo-treated patients (16%); p < 0.0001 (Figure 1). RELISTOR-treated patients also had significantly higher rates of laxation within 4 hours after at least 2 of the first 4 doses (52%) than did placebo-treated patients (9%); p < 0.0001. In both studies, in approximately 30% of patients, laxation was reported within 30 minutes of a dose of RELISTOR.

Figure 1: Laxation Response Within 4 Hours of the First Dose

Laxation Response Within 4 Hours of the First Dose - Illustration

In both studies, there was no evidence of differential effects of age or gender on safety or efficacy. No meaningful subgroup analysis could be conducted on race because the study population was predominantly Caucasian (88%).

Durability of Response

Durability of response was explored in Study 2 and the laxation response rate was consistent from dose 1 through dose 7 over the course of the 2-week, double-blind period.

The efficacy and safety of methylnaltrexone bromide was also demonstrated in open-label treatment administered from Day 2 through Week 4 in Study 1, and in two open-label extension studies (Study 1EXT and Study 2EXT) in which RELISTOR was given as needed for up to 4 months. During open-label treatment, patients maintained their regular laxative regimen. A total of 136, 21, and 82 patients received at least 1 open-label dose in studies 1, 1EXT, and 2EXT, respectively. Laxation response was also explored in this open-label setting and appeared to be maintained over the course of 3 to 4 months of open-label treatment.

Opioid Use and Pain Scores

No relationship between baseline opioid dose and laxation response in methylnaltrexone bromide-treated patients was identified in exploratory analyses of these studies. In addition, median daily opioid dose did not vary meaningfully from baseline in either RELISTOR-treated patients or in placebo-treated patients. There were no clinically relevant changes in pain scores from baseline in either the methylnaltrexone bromide or placebo-treated patients.

This monograph has been modified to include the generic and brand name in many instances.

Patient Information

RELISTOR®
(rel - i – store)
(methylnaltrexone bromide) Subcutaneous Injection

Read this Medication Guide before you start using RELISTOR and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about RELISTOR?

RELISTOR can cause serious side effects, including:

  • Tear in your stomach or intestinal wall (perforation). Stomach pain that is severe can be a sign of a serious medical condition. If you get stomach pain that does not go away, stop taking RELISTOR and get emergency medical help right away.
  • Diarrhea that is severe or that will not go away. Stop using RELISTOR and call your healthcare provider if you get diarrhea that is severe or that does not go away during treatment with RELISTOR.
  • Opioid withdrawal. You may have symptoms of opioid withdrawal during treatment with RELISTOR including sweating, chills, diarrhea, stomach pain, anxiety, and yawning. Tell your healthcare provider if you have any of these symptoms.

What is RELISTOR?

RELISTOR is a prescription medicine used to treat constipation that is caused by prescription pain medicines called opioids, in adults:

  • with long-lasting (chronic) pain that is not caused by cancer
  • receiving treatment for advanced illness, when other medicines for constipation have not worked well enough

It is not known if RELISTOR is safe and effective if used for longer than 4 months in people with advanced illness.

It is not known if RELISTOR is safe and effective in children.

Who should not use RELISTOR?

Do not use RELISTOR if you have a bowel blockage (intestinal obstruction) or have a history of bowel blockage.

What should I tell my healthcare provider before using RELISTOR?

Before you start using RELISTOR, tell your healthcare provider about all of your medical conditions, including if you:

  • have kidney problems
  • have any stomach or bowel (intestines) problems, including stomach ulcer, Crohn's disease, diverticulitis, cancer of the stomach or bowel, or Ogilvie's syndrome
  • are pregnant or plan to become pregnant. Taking RELISTOR during pregnancy may cause opioid withdrawal symptoms in your unborn baby. Tell your healthcare provider right away if you become pregnant during treatment with RELISTOR.
  • are breastfeeding or plan to breastfeed. It is not known if RELISTOR passes into your breast milk. Taking RELISTOR while you are breastfeeding may cause opioid withdrawal in your baby. You and your healthcare provider should decide if you will take RELISTOR or breastfeed. You should not do both.

Tell your healthcare provider about all of the medicines you take, including prescription and overthe- counter medicines, vitamins, and herbal supplements.

How should I use RELISTOR?

See the detailed Instructions for Use that comes with RELISTOR for information about how to prepare and inject RELISTOR, and properly throw away (dispose of) used needles and syringes the right way.

  • RELISTOR is injected under the skin (subcutaneous injection) of the upper arm, stomach-area (abdomen), or thigh.
  • Inject RELISTOR exactly as your healthcare provider tells you.
  • Stay close to a toilet after using RELISTOR.
  • Stop using RELISTOR if you stop taking your prescription opioid pain medicine. Tell your healthcare provider if your pain medication changes.
  • If you take too much RELISTOR, call your healthcare provider or go to the nearest emergency room right away.
  • If you use RELISTOR for long-lasting (chronic) pain that is not caused by cancer:
    • RELISTOR has been shown to be effective in people who have taken opioid pain medicines for at least 4 weeks to treat long-lasting (chronic) pain not caused by cancer.
    • Stop taking other laxatives before you start treatment with RELISTOR. You may use other laxatives if RELISTOR does not work after 3 days of treatment.
    • Inject 1 dose of RELISTOR each day.
  • If you use RELISTOR and are receiving treatment for advanced illness:
    • Inject 1 dose of RELISTOR every other day, as needed. You should not inject more than 1 dose of RELISTOR in a 24-hour period.

What are the possible side effects of RELISTOR?

See “What is the most important information I should know about RELISTOR?”

  • The most common side effects of RELISTOR in people with long-lasting (chronic) pain that is not caused by cancer include: stomach-area (abdomen) pain, nausea, diarrhea, sweating, hot flush, tremor, and chills.
  • The most common side effects of RELISTOR in people receiving treatment for their advanced illness include: stomach-area (abdomen) pain, gas, nausea, dizziness, and diarrhea.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of RELISTOR.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Salix Pharmaceuticals at 1-800-508-0024.

How should I store RELISTOR?

  • Store RELISTOR vials and pre-filled syringes at room temperature between 68°F to 77°F (20°C to 25°C).
  • Do not freeze RELISTOR.
  • Keep RELISTOR away from light until you are ready to use it.

If RELISTOR has been drawn into a syringe and you are unable to use the medicine right away, keep the syringe at room temperature for up to 24 hours.

Keep RELISTOR and all medicines, needles and syringes out of the reach of children.

General information about RELISTOR

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RELISTOR for a condition for which it was not prescribed. Do not give RELISTOR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RELISTOR that is written for health professionals.

What are the ingredients in RELISTOR?

Active ingredient: methylnaltrexone bromide

Inactive ingredients: sodium chloride, edetate calcium disodium USP, glycine hydrochloride. During manufacture, the pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.

Manufactured for: Salix Pharmaceuticals, Inc., Raleigh, NC 27615. Under license from: Progenics Pharmaceuticals, Inc., Tarrytown, NY 10591. Revised: September 2014

Instructions for Use

RELISTOR®
(rel-i-store) (methylnaltrexone bromide)

Subcutaneous Injection

Pre-filled Syringe

Read this Instructions for Use before you start using RELISTOR and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

The following instructions explain how to prepare and give an injection of RELISTOR the right way, when using a pre-filled syringe of RELISTOR.

Important information:

  • Do not use a RELISTOR pre-filled syringe and attached needle more than 1 time, even if there is medicine left in the syringe. See Step 4 “Dispose of used pre-filled syringes and needles.”
  • Safely throw away RELISTOR pre-filled syringes and attached needle after use.
  • To avoid needle-stick injuries, do not recap used needles.
  • Avoid touching the trigger fingers of the RELISTOR pre-filled syringe to keep from activating the needle guard (safety device) too soon. The needle guard is activated by pressure from the plunger on the trigger fingers (See Figure A).

Gather the supplies you will need for your injection (See Figure A). These include:

  • 1 RELISTOR pre-filled syringe with attached needle
  • 1 alcohol swab
  • 1 cotton ball or gauze
  • 1 adhesive bandage
  • a container to dispose of used pre-filled syringes and needles. See Step 4: “Dispose of used pre-filled syringes and needles.”

Figure A

View Enlarged Table

Step 1: Choose and prepare the injection site

  • Choose an injection site on your stomach-area (abdomen), thighs, or upper arms. See the shaded areas in Figures B and C below. Do not inject at the exact same spot each time (rotate injection sites). Do not inject into areas where the skin is tender, bruised, red or hard. Avoid areas with scars or stretch marks.

Figure B - Abdomen or thigh – use these sites when injecting yourself or another person.

Figure C - Upper arm – use this site only when injecting another person.

Figure B & Figure C

Injection site - Illustration
  • Clean the injection site with an alcohol swab and let it air dry. Do not touch this area again before giving the injection (See Figure D).

Figure D

Clean the injection site - Illustration

Step 2: Prepare the pre-filled syringe

  • Choose a flat, clean, well-lit work surface.
  • Wash your hands with soap and water before preparing for the injection.
  • Look at the pre-filled syringe of RELISTOR (See Figure E). Make sure that the dose prescribed by your healthcare provider matches the dose on the prefilled syringe label. Look at the plunger rod of the syringe. If the dose prescribed by your healthcare provider is 8 mg, the plunger rod will be yellow; if the prescribed dose is 12 mg, the plunger rod of the syringe will be dark blue (See Figure E).

Figure E

Pre-filled syringe of RELISTOR - Illustration
  • The liquid in the pre-filled syringe should be clear and colorless to pale yellow, and should not have any particles in it. Do not use the pre-filled syringe if it looks discolored, cloudy, or has any particles.
  • Use one hand to firmly hold the barrel of the pre-filled syringe. Use your other hand to pull the needle cap straight off (Figure F). Do not touch the needle or allow it to touch anything.

Figure F

Pull the needle cap straight off - Illustration

Step 3: Inject RELISTOR

  • Use one hand to pinch the skin around the injection site (See Figure G).

Figure G

pinch the skin around the injection site - Illustration
  • Use your other hand to hold the pre-filled syringe. Insert the full length of the needle into the skin at a 45-degree angle with a quick “dart-like” motion (See Figure H).

Figure H

Insert the full length of the needle - Illustration
  • Let go of the skin and slowly push the plunger in with your thumb until the pre-filled syringe is empty (See Figure I). This will release the needle guard (safety device).

Figure I

Slowly push the plunger in - Illustration
  • Continue to hold pressure on the plunger with your thumb and quickly pull the needle out of the skin. Be careful to keep the needle at the same angle as it was inserted. Remove your thumb from the plunger to allow the protective sleeve to cover the needle (See Figure J). There may be a little bleeding at the injection site.

Figure J

Allow the protective sleeve to cover the needle - Illustration
  • Hold a cotton ball or gauze over the injection site (See Figure K). Do not rub the injection site. Apply an adhesive bandage to the injection site if needed.

Figure K

Hold a cotton ball or gauze over the injection site - Illustration

Step 4: Dispose of used pre-filled syringes and needles

  • Do not re-use the pre-filled syringe and attached needle.
  • To avoid needle-stick injuries, do not recap used needles.
  • Put your used pre-filled syringes and attached needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.
  • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
    • made of a heavy-duty plastic,
    • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
    • upright and stable during use,
    • leak-resistant, and
    • properly labeled to warn of hazardous waste inside the container.
  • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
  • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
  • If you have any questions, talk to your healthcare provider or pharmacist.

How should I store RELISTOR?

  • Store pre-filled syringes at room temperature between 68°F to 77°F (20°C to 25°C).
  • Do not freeze RELISTOR.
  • Keep RELISTOR away from light until you are ready to use it.

Keep RELISTOR and all medicines, needles and syringes out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Instructions for Use

RELISTOR®
(rel-i-store)
(methylnaltrexone bromide)

Subcutaneous Injection

Vial and Syringe with Retractable Needle in Tray

Read this Instructions for Use before you start using RELISTOR and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

The following instructions explain how to prepare and give an injection of RELISTOR the right way, when using a RELISTOR tray containing a syringe with a retractable needle. A retractable needle is one that is pulled back so that it is covered after use, to prevent needle-stick injury.

Important information:

  • Do not use a RELISTOR vial more than 1 time, even if there is medicine left in the vial.
  • If RELISTOR has been drawn into a syringe and you are unable to use the medicine right away, carefully recap the needle and keep the syringe at room temperature for up to 24 hours. For more information about how to store RELISTOR, see the section called “How should I store RELISTOR?” at the end of this Instructions for Use.
  • Safely throw away RELISTOR vials after use.
  • Do not reuse syringes and needles. See Step 5: “Dispose of used syringes and needles” for information about how to safely throw away used needles and syringes.
  • To avoid needle-stick injuries, do not recap used needles.

Your tray should include (See Figure A):

  • 1 RELISTOR vial
  • 1 1 mL syringe with retractable needle (VanishPoint®)
  • 2 alcohol swabs

You will also need:

  • 1 cotton ball or gauze
  • 1 adhesive bandage
  • a container to dispose of your used syringes and needles. See Step 5: “Dispose of used syringes and needles.”

Figure A

View Enlarged Table

Step 1: Choose and prepare the injection site

  • Choose an injection site on your stomach-area (abdomen), thighs, or upper arms. See the shaded areas in Figures B and C below. Do not inject at the exact same spot each time (rotate injection sites). Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid areas with scars or stretch marks.

Figure B - Abdomen or thigh – use these sites when injecting yourself or another person.

Figure C - Upper arm – use this site only when injecting another person.

Figure B & Figure C

Choose an injection site - Illustration
  • Clean the injection site with an alcohol swab and let it air dry. Do not touch this area again before giving the injection (See Figure D).

Figure D

Clean the injection site - Illustration

Step 2: Prepare the injection

  • Choose a flat, clean, well-lit work surface.
  • Wash your hands with soap and water before preparing for the injection.
  • Look at the vial of RELISTOR (See Figure E). The liquid in the vial should be clear and colorless to pale yellow, and should not have any particles in it. Do not use the vial if it looks discolored, cloudy, or has any particles.

Figure E

vial of RELISTOR - Illustration

Step 3: Prepare the syringe

  • Remove the cap from the vial containing RELISTOR (See Figure F).

Figure F

Remove the cap - Illustration
  • Wipe the rubber stopper with an alcohol swab (See Figure G).

Figure G

Wipe the rubber stopper - Illustration
  • Firmly hold the barrel of the syringe with one hand. With your other hand, pull the needle cap straight off (See Figure H). Do not touch the needle or allow it to touch anything.

Figure H

Pull the needle cap straight off - Illustration
  • Carefully pull back on the plunger to the line that matches the dose prescribed by your healthcare provider (See Figures I and J). For most people, this will be the 0.4 mL mark which is an 8 mg dose or the 0.6mL mark which is a 12 mg dose.

Figure I

pull back on the plunger to the required dose - Illustration

Figure J

pull back on the plunger to the required dose - Illustration
  • Use one hand to hold the vial steady. Use your other hand to insert the needle straight down into the rubber top of the RELISTOR vial (See Figure K). Do not insert it at an angle. This may cause the needle to bend or break. You will feel some resistance as the needle passes through the rubber top.

Figure K

Insert the needle straight down - Illustration
  • Gently push down on the plunger until you feel resistance, and most of the air has gone from the syringe into the vial (See Figure L). Stop pushing down on the plunger when you feel resistance. If you continue to push down on the plunger when you feel resistance, the needle will pull back (retract) into the syringe barrel.

Figure L

Gently push down on the plunger - Illustration
  • With the needle still in the vial, turn the vial and syringe upside down. Hold the syringe at eye level. Make sure the tip of the needle is in the fluid. Slowly pull back on the plunger (See Figure M) until the tip lines up with the mark that matches your prescribed dose. For most people, this will be the 0.4 mL mark which is an 8 mg dose or the 0.6 mL mark which is a 12 mg dose.

Figure M

Slowly pull back on the plunger - Illustration
  • You may see some fluid or bubbles inside the vial when the syringe is filled. This is normal.
  • With the needle still in the vial, gently tap the syringe to make any air bubbles rise to the top (See Figure N).

Figure N

Gently tap the syringe - Illustration
  • Gently push the plunger up until all air bubbles are out of the syringe (See Figure O). A small air bubble may stay in the syringe. This is okay and it will not affect the dose of medicine in the syringe.

Figure O

Gently push the plunger up - Illustration
  • Make sure the tip of the needle is in the fluid. Slowly pull back the plunger to draw the right amount of liquid back into the syringe (See Figure P).

Figure P

Slowly pull back the plunger - Illustration

Check to be sure that you have the right dose of RELISTOR in the syringe.

  • Slowly withdraw the needle from the vial. Do not touch the needle or allow it to touch anything. Safely throw away the vial with any unused medicine.

Step 4: Inject RELISTOR

  • Use one hand to pinch the skin around the injection site (See Figure Q).

Figure Q

Pinch the skin around the injection site - Illustration
  • Use your other hand to hold the syringe. Insert the full length of the needle into the skin at a 45-degree angle with a quick “dart-like” motion (See Figure R).

Figure R

Insert the full length of the needle into the skin - Illustration
  • Let go of the skin and slowly push in on the plunger past the resistance point, until the syringe is empty and you hear a click (See Figure S).

Figure S

slowly push in on the plunger - Illustration
  • The click sound means that the needle (See Figure T) has been pulled back (retracted) into the syringe barrel (See Figure U). You can now remove the syringe from your skin.

Figure T & Figure U

Needle retracted - Illustration
  • Hold a cotton ball or gauze over the injection site (See Figure V). Do not rub the injection site. Apply an adhesive bandage to the injection site if needed.

Figure V

Hold a cotton ball or gauze over the injection site - Illustration

Step 5: Dispose of used syringes and needles

  • Do not re-use syringes or needles.
  • To avoid needle-stick injuries, do not recap used needles.
  • Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.
  • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
    • made of a heavy-duty plastic,
    • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
    • upright and stable during use,
    • leak-resistant, and
    • properly labeled to warn of hazardous waste inside the container.
  • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
  • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
  • If you have any questions, talk to your healthcare provider or pharmacist.

How should I store RELISTOR?

Store RELISTOR vials at room temperature between 68°F to 77°F (20°C to 25°C).

Do not freeze RELISTOR.

Keep RELISTOR away from light until you are ready to use it.

If RELISTOR has been drawn into a syringe and you are unable to use the medicine right away, keep the syringe at room temperature for up to 24 hours.

Keep RELISTOR and all medicines, needles and syringes out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Instructions for Use

RELISTOR®
(rel-i-store)
(methylnaltrexone bromide)

Subcutaneous Injection

Vial

Read this Instructions for Use before you start using RELISTOR and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

The following instructions explain how to prepare and give an injection of RELISTOR the right way, when using a vial of RELISTOR.

Important information:

  • Use the syringes and needles prescribed by your healthcare provider.
  • Do not use a RELISTOR vial more than 1 time, even if there is medicine left in the vial.
  • If RELISTOR has been drawn into a syringe and you are unable to use the medicine right away, carefully recap the needle and keep the syringe at room temperature for up to 24 hours. For more information about how to store RELISTOR, see the section “How should I store RELISTOR?” at the end of this Instructions for Use.
  • Safely throw away RELISTOR vials after use.
  • Do not re-use syringes or needles. See Step 5 “Dispose of used syringes and needles” for information about how to safely throw away used needles and syringes.
  • To avoid needle-stick injuries, do not recap used needles.

Gather the supplies you will need for your injection (See Figure A.). These include:

  • 1 RELISTOR vial
  • 1 1 mL syringe with a 27-gauge, ½ inch needle for subcutaneous use
  • 2 alcohol swabs
  • 1 cotton ball or gauze
  • 1 adhesive bandage
  • a container to dispose of used syringes and needles. See Step 5: “Dispose of used syringes and needles.”

Figure A

View Enlarged Table

Step 1: Choose and prepare the injection site

  • Choose an injection site on your stomach-area (abdomen), thighs, or upper arms. See the shaded areas in Figures B and C below. Do not inject at the exact same spot each time (rotate injection sites). Do not inject into areas where the skin is tender, bruised, red or hard. Avoid areas with scars or stretch marks.

Figure B - Abdomen or thigh – use these sites when injecting yourself or another person.

Figure C -Upper arm – use this site only when injecting another person.

Figure B & Figure C

Choose an injection site - Illustration
  • Clean the injection site with an alcohol swab and let it air dry. Do not touch this area again before giving the injection (See Figure D).

Figure D

Clean the injection site - Illustration

Step 2: Prepare the injection

  • Choose a flat, clean, well-lit work surface.
  • Wash your hands with soap and water before preparing for the injection.
  • Look at the vial of RELISTOR (See Figure E). The liquid in the vial should be clear and colorless to pale yellow, and should not have any particles in it. Do not use the vial if it looks discolored, cloudy, or has any particles.

Figure E

Vial of RELISTOR - Illustration

Step 3: Prepare the syringe

  • Remove the cap from the RELISTOR vial (See Figure F).

Figure F

Remove the cap - Illustration
  • Wipe the rubber stopper with an alcohol swab (See Figure G).

Figure G

Wipe the rubber stopper - Illustration
  • Firmly hold the barrel of the syringe with one hand. With your other hand, pull the needle cap straight off (See Figure H). Do not touch the needle or allow it to touch anything.

Figure H

Pull the needle cap straight off - Illustration
  • Carefully pull back on the plunger to the line that matches the dose prescribed by your healthcare provider (See Figures I and J). For most people, this will be the 0.4 mL mark which is an 8 mg dose or the 0.6 mL mark which is a 12 mg dose.

Figure I

Pull back on the plunger to the required dosage mark - Illustration

Figure J

Pull back on the plunger to the required dosage mark - Illustration
  • Use one hand to hold the vial steady. Use your other hand to insert the needle straight down into the rubber top of the vial (See Figure K). Do not insert it at an angle. This may cause the needle to bend or break. You will feel some resistance as the needle passes through the rubber top.

Figure K

Insert the needle straight down - Illustration
  • Gently push down the plunger until all of the air has gone from the syringe into the vial (See Figure L).

Figure L

Gently push down the plunger - Illustration
  • With the needle still in the vial, turn the vial and syringe upside down. Hold the syringe at eye level. Make sure the tip of the needle is in the fluid. Slowly pull back on the plunger (See Figure M) until the tip lines up with the mark that matches your prescribed dose. For most people, this will be the 0.4 mL mark which is an 8 mg dose or the 0.6 mL mark which is a 12 mg dose.

Figure M

Turn the vial and syringe upside down - Illustration
  • You may see some fluid or bubbles inside the vial when the syringe is filled. This is normal.
  • With the needle still in the vial, gently tap the side of the syringe to make any air bubbles rise to the top (See Figure N).

Figure N

Gently tap the side of the syringe - Illustration
  • Slowly push the plunger up until all air bubbles are out of the syringe (See Figure O). A small air bubble may stay in the syringe. This is okay and it will not affect the dose of medicine in the syringe.

Figure O

Slowly push the plunger up -  Illustration
  • Make sure the tip of the needle is in the fluid. Slowly pull back the plunger to draw the right amount of liquid back into the syringe (See Figure P).

Figure P

Pull back the plunger to draw the right dosage - Illustration

Check to be sure that you have the right dose of RELISTOR in the syringe.

  • Slowly withdraw the needle from the vial. Do not touch the needle or allow it to touch anything. Safely throw away the vial with any unused medicine.

Step 4: Inject RELISTOR

  • Use one hand to pinch the skin around the injection site (See Figure Q).

Figure Q

Pinch the skin around the injection site - Illustration
  • Use your other hand to hold the syringe. Insert the full length of the needle into the skin at a 45-degree angle with a quick “dart-like” motion (See Figure R).

Figure R

Insert the full length of the needle into the skin - Illustration
  • Let go of the skin and slowly push in on the plunger until the syringe is empty (Figure S).

Figure S

Slowly push in on the plunger - Illustration
  • When the syringe is empty, quickly pull the needle out of the skin, being careful to keep it at the same angle as it was inserted. There may be a little bleeding at the injection site.
  • Hold a cotton ball or gauze over the injection site (Figure T). Do not rub the injection site. Apply an adhesive bandage to the injection site if needed.

Figure T

Hold a cotton ball or gauze over the injection site - Illustration

Step 5: Dispose of used syringes and needles

  • Do not re-use a syringe or needle.
  • To avoid needle-stick injuries, do not recap a used needle.
  • Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.
  • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
    • made of a heavy-duty plastic,
    • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
    • upright and stable during use,
    • leak-resistant, and
    • properly labeled to warn of hazardous waste inside the container.
  • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
  • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
  • If you have any questions, talk to your healthcare provider or pharmacist.

How should I store RELISTOR?

  • Store RELISTOR vials at room temperature between 68°F to 77°F (20°C to 25°C).
  • Do not freeze RELISTOR.
  • Keep RELISTOR away from light until you are ready to use it.
  • If RELISTOR has been drawn into a syringe and you are unable to use the medicine right away, keep the syringe at room temperature for up to 24 hours.

Keep RELISTOR and all medicines, needles and syringes out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

No Information Available!

Consumer Overview Side Effect

No Information Available!

Consumer Overview Missed Dose

No Information Available!

Patient Detailed Side Effect

Brand Names: Relistor

Generic Name: methylnaltrexone (Pronunciation: METh IL nal TREX own)

  • What is methylnaltrexone (Relistor)?
  • What are the possible side effects of methylnaltrexone (Relistor)?
  • What is the most important information I should know about methylnaltrexone (Relistor)?
  • What should I discuss with my health care provider before receiving methylnaltrexone (Relistor)?
  • How is methylnaltrexone used (Relistor)?
  • What happens if I miss a dose (Relistor)?
  • What happens if I overdose (Relistor)?
  • What should I avoid while using methylnaltrexone (Relistor)?
  • What other drugs will affect methylnaltrexone (Relistor)?
  • Where can I get more information?

What is methylnaltrexone (Relistor)?

Methylnaltrexone is a special narcotic drug that blocks certain effects of other narcotic medicines.

Methylnaltrexone reduces constipation caused by narcotic medications that are often used to treat pain in people with terminal illness.

Methylnaltrexone works by preventing this side effect without reducing the pain-relieving effects of the narcotic.

Methylnaltrexone is usually given after laxatives have been tried without successful treatment of constipation.

Methylnaltrexone may also be used for purposes not listed in this medication guide.

What are the possible side effects of methylnaltrexone (Relistor)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have severe or ongoing diarrhea, stomach pain that will not go away, black or bloody stools, coughing up blood, or nausea or vomiting that are new or worsening symptoms.

Less serious side effects may include:

  • stomach pain, gas;
  • mild nausea or diarrhea;
  • dizziness; or
  • increased sweating.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Read the Relistor (methylnaltrexone bromide) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about methylnaltrexone (Relistor)?

You should not use this medication if you are allergic to methylnaltrexone, or if you have a blockage in your stomach or intestines.

Before you use methylnaltrexone, tell your doctor if you have severe or ongoing diarrhea.

Prepare your dose in a syringe only when you are ready to give yourself an injection. After loading a syringe, if you cannot give the injection right away keep it at room temperature and use it within 24 hours.

Methylnaltrexone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Side Effects Centers
  • Relistor

Patient Detailed How Take

What should I discuss with my health care provider before receiving methylnaltrexone (Relistor)?

You should not use this medication if you are allergic to methylnaltrexone, or if you have a blockage in your stomach or intestines.

To make sure you can safely use methylnaltrexone, tell your doctor if you have any of these other conditions:

  • cancer;
  • a stomach ulcer; or
  • colitis or other intestinal disorder.

FDA pregnancy category B. Methylnaltrexone is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether methylnaltrexone passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How is methylnaltrexone used (Relistor)?

Methylnaltrexone is injected under the skin. You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

This medication is usually given once every other day, but not more often than once every 24 hours.

Methylnaltrexone can produce a bowel movement within 30 minutes after injection.

Prepare your dose in a syringe only when you are ready to give yourself an injection. After loading a syringe, if you cannot give the injection right away keep it at room temperature and use it within 24 hours.

Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

Each single use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Methylnaltrexone should look clear or slightly yellow in color. Do not use the medication if it has changed colors or has particles in it. Call your doctor for a new prescription.

Store at room temperature away from moisture, heat, and light. Do not freeze.

Side Effects Centers
  • Relistor

Patient Detailed Avoid Taking

What happens if I miss a dose (Relistor)?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Do not use this medication more than once in a 24-hour period.

What happens if I overdose (Relistor)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include extreme dizziness, or feeling like you might pass out.

What should I avoid while using methylnaltrexone (Relistor)?

Methylnaltrexone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Do not use any other laxatives that your doctor has not prescribed.

What other drugs will affect methylnaltrexone (Relistor)?

Before receiving methylnaltrexone, tell your doctor if you use any narcotic medication, such as:

  • buprenorphine (Buprenex, Subutex);
  • butorphanol (Stadol);
  • codeine (Tylenol with codeine);
  • hydrocodone (Lortab, Vicodin);
  • hydromorphone (Dilaudid);
  • levorphanol (Levo-Dromoran);
  • meperidine (Demerol);
  • methadone (Dolophine, Methadose);
  • morphine (Kadian, MS Contin, Roxanol);
  • nalbuphine (Nubain);
  • naloxone (Narcan);
  • oxycodone (OxyContin, Roxicodone, Percocet);
  • oxymorphone (Numorphan); or
  • propoxyphene (Darvon, Darvocet).

This list is not complete and other drugs may interact with methylnaltrexone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about methylnaltrexone.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 4.03. Revision date: 4/18/2012.

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