Consumer medicine information

Relistor

Methylnaltrexone bromide

BRAND INFORMATION

Brand name

Relistor

Active ingredient

Methylnaltrexone bromide

Schedule

What is in this leaflet

This leaflet answers some common questions about RELISTOR. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking RELISTOR against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist. Keep this leaflet with the medicine. You may need to read it again.

What RELISTOR is used for

The name of your medicine is RELISTOR. It contains the active ingredient called methylnaltrexone bromide.

RELISTOR is used to relieve constipation caused by strong pain relievers called opiates (for example, morphine, codeine) prescribed by your doctor. RELISTOR works by stimulating the muscle contractions of the digestive tract. This helps waste move more easily through the intestines. RELISTOR is used when other medicines to treat constipation, called laxatives, have not worked well enough.

Your doctor may have prescribed RELISTOR for another reason. Ask your doctor if you have any questions about why RELISTOR has been prescribed for you.

There is no evidence that RELISTOR is addictive.

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

Before you use RELISTOR

When you must not use it

Do not use RELISTOR if:

You have an allergy to RELISTOR or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include wheezing, shortness of breath, difficulty breathing or a tight feeling in your chest, swelling of the face, lips, tongue or other parts of the body, rash, itching, hives or flushed red skin, dizziness or light-headedness.

You think you have any acute abdominal condition other than constipation, or if you experience persistent stomach pain, nausea (feeling sick in the stomach) or vomiting that is new or has worsened.

Symptoms of an acute abdominal condition include tenderness of the abdomen, increasing abdominal pain, increased abdominal bloating.

The packaging is torn or shows signs of tampering.
The expiry date (EXP) printed on the pack has passed.

If you use RELISTOR after the expiry date has passed, it may have no effect at all, or worse, have an entirely unexpected effect.

If you are not sure whether you should start using RELISTOR, contact your doctor.

Before you use it

Tell your doctor if:

You have any allergies to the following:

Any other medicines
Any other substances, such as foods, preservatives or dyes.

You have severe kidney or liver disease
You have a colostomy, a peritoneal catheter, or already known disease called diverticular disease or faecal impaction
You have suffered from constipation before you had to take opiates (for pain)
You are pregnant or intend to become pregnant

The effects of RELISTOR in pregnant women are not known, and so the use of RELISTOR during pregnancy is not recommended unless clearly necessary.

You are breast-feeding or plan to breast-feed

Women using RELISTOR should not breast-feed, since it is not known if RELISTOR passes into human breast milk.

If you have not told your doctor about any of the above, tell them before you start using RELISTOR.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may affect the way others work. Your doctor or pharmacist will be able to tell you what to do when using RELISTOR with other medicines. RELISTOR may interact with other medicines such as:

bevacizumab, used to treat some cancers
non-steroidal anti inflammatory drugs (NSAIDs), used to treat inflammation, pain and fever
steroids, used to treat inflammation.

How to use RELISTOR

RELISTOR contains no additives that would prevent the growth of bacteria. For this reason, each vial of RELISTOR is for single use only, in one patient only. Discard any residue.

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

How much to use

Your doctor will determine what dose you should take. Never inject more than the dose recommended by your doctor.

How to use it

RELISTOR is given by an injection under the skin (by subcutaneous injection) in either (1) your upper legs (thighs), (2) your abdomen (stomach), and (3) your upper arm (if not self-injecting). RELISTOR can be taken with or without food.

See INSTRUCTIONS FOR PREPARING AND GIVING AN INJECTION OF RELISTOR.

It is recommended to move to a different site each time an injection is given. Do not inject into areas where the skin is tender, bruised, red, or hard, taking care to avoid areas with scars or stretch marks.

Most patients who respond to RELISTOR have a bowel movement within a few minutes to a few hours of the injection; therefore it is recommended to have a toilet facility or bedpan near you.

When to use it

RELISTOR should be used as a single dose on alternate days. Doses may also be given with longer intervals, as needed. If there has been no bowel movement within 24 hours of the last dose, an additional dose may be given. No more than one dose of RELISTOR should be given in a 24-hour period.

How long to take it

You should continue to use RELISTOR for as long as your doctor recommends.

If you forget to take it

If you forget to give yourself an injection, you should contact your doctor or pharmacist as soon as possible.

Do not use a double dose to make up for the dose that you missed.

If you take too much (overdose)

If you have used more RELISTOR than you should (either by injecting too much on a single occasion or by using more than one injection in 24 hours), immediately telephone your doctor or the Poisons Information Centre (in Australia Tel 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have used too much RELISTOR. Do this even if there are no signs of discomfort or poisoning. Always take the labelled medicine carton with you, even if it is empty. You may need urgent medical attention. There is very limited data on overdose with RELISTOR. Ask your doctor if you have any concerns.

While you are using RELISTOR

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are using RELISTOR.

Tell your doctor if RELISTOR is not making your condition better.

Be careful driving or operating dangerous machinery until you know how it affects you. RELISTOR may cause dizziness, and this may have an effect on driving and use of machines.

Tell your doctor if you experience severe or persistent diarrhoea whilst using RELISTOR. It is important to be near a toilet with assistance available if necessary, since bowel movement may happen within 30 minutes after injection of the medicine.

Stop using RELISTOR and tell your doctor if you get abdominal pain that will not go away or nausea or vomiting that is new or worse. RELISTOR may increase the risk of stomach or intestinal perforation, especially in the presence of conditions that weaken the stomach or intestinal wall, such as cancer and ulcers of the stomach or intestine.

Things you must not do

Do not give RELISTOR to anyone else even if they have the same condition as you.

Do not use RELISTOR to treat any other complaints unless your doctor tells you to.

Side Effects

Check with your doctor as soon as possible if you have any problems while taking RELISTOR, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like all medicines, RELISTOR can cause side effects, although not everyone gets them.

As with other injected medicines, common injection site reactions (e.g. stinging, burning, pain, redness, oedema) may occur.

The most common side effects likely to occur in more than one in ten patients receiving RELISTOR are:

Abdominal pain (belly ache)
Nausea (feeling sick in the stomach)
Flatulence (passing wind)
Diarrhoea (passing of frequent watery stools)
Excessive sweating

Common side effects likely to occur in more than one in 100 patients, but in less than one in ten patients receiving RELISTOR are:

Dizziness (light-headed)

Other side effects may occur when using RELISTOR.

Tell your healthcare professional if you have any side effect that bothers you or that does not go away or that gets serious.

How to store RELISTOR

Keep out of the reach and sight of children.

RELISTOR should be stored below 30°C and should be protected from light.

Do not use RELISTOR after the expiry date, which is stated on the carton and vial.

Only use RELISTOR if the solution is clear, colourless to pale yellow and does not contain lumps or flakes or particles.

Disposal

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

The syringe and needle should NEVER be reused. NEVER recap the needle. Needles should be disposed of properly in a "puncture-resistant container" or as per instructions from your doctor, nurse or pharmacist.

Product Description

What it looks like

The following packs are available:

A single vial.
A convenience pack containing 7 cartons. Each carton contains:

One 12 mg/0.6 ml single-use vial (20 mg/ml), one 1 ml syringe, two alcohol swabs.

Ingredients

The active substance is methylnaltrexone bromide.

The other ingredients are sodium chloride, sodium calcium edetate, glycine hydrochloride, and water for injections. During manufacture, the pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.

RELISTOR does not contain lactose, gluten, tartrazine or any other azo dyes.

Supplier

Link Medical Products Pty Ltd
5 Apollo Street
Warriewood, NSW 2102
Australia

Link Pharmaceuticals Ltd
Suite 32, Level 26,
PwC Tower,
188 Quay Street,
Auckland, 1010
New Zealand

Australian Registration Number

12 mg solution; AUST R 144062

® Registered Trademark

This document was last revised in June 2020.

Published by MIMS November 2020

BRAND INFORMATION

Brand name

Relistor

Active ingredient

Methylnaltrexone bromide

Schedule

1 Name of Medicine

Methylnaltrexone bromide.

2 Qualitative and Quantitative Composition

Each single-use vial of Relistor injection contains 12 mg of methylnaltrexone bromide in 0.6 mL of water for injections, with a concentration of 20 mg/mL of methylnaltrexone bromide.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Relistor is a sterile, clear and colourless to pale yellow aqueous solution.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Usual dosage.

For subcutaneous injection only.
Contains no antimicrobial agent. Relistor is for single use in one patient only. Discard any residue.
Relistor should be injected in the upper arm, abdomen or thigh. It is recommended to move to a different site each time an injection is given. Avoid repeated injections at the exact same spot previously used. Do not inject into areas where the skin is tender, bruised, red or hard. Avoid areas with scars or stretch marks.
Relistor is administered as a single dose on alternate days. Doses may also be given with longer intervals, as needed. If there has been no bowel movement within 24 hours of the last dose, an additional dose may be given. In clinical trials, Relistor was administered concomitantly with a laxative regimen.
Relistor can be injected without regard to food. The recommended dose of Relistor is detailed in Table 1.

Dosage adjustment in renal impairment.

In patients with severe renal impairment (creatinine clearance less than 30 mL/min) reduce the dose of Relistor by one-half. No dose adjustment is required in patients with mild or moderate renal impairment. There are no data available from patients with end-stage renal impairment on dialysis and, therefore, is not recommended in these patients.

Dosage adjustment in hepatic impairment.

No dose adjustment is required for patients with mild or moderate hepatic impairment. There are no data available from patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, is not recommended in these patients.

Paediatric use.

Safety and efficacy of Relistor have not been established in paediatric patients.

Use in elderly patients.

No dose adjustment is recommended based on age.

4.3 Contraindications

Relistor is contraindicated in patients with:
known hypersensitivity to the drug or any of its components;
known or suspected mechanical gastrointestinal obstruction or acute surgical abdomen.

4.4 Special Warnings and Precautions for Use

Relistor has been studied in a small population of patients who were receiving palliative care and who had insufficient response to laxative therapy. Use of Relistor beyond 4 months has not been studied. Safety and efficacy with longer term use and in other patient groups have not been established.

Use with caution in the following circumstances.

If severe or persistent diarrhoea occurs during treatment, patients should be advised not to continue therapy with Relistor and consult their physician.
Cases of gastrointestinal tract perforations have been reported in association with use of methylnaltrexone bromide in patients with advanced illness and conditions that may be associated with localised or diffuse reduction of structural integrity in the wall of the gastrointestinal tract [(e.g. cancer, peptic ulcer, pseudo-obstruction and concomitant medications known to cause gastrointestinal tract perforations e.g. bevacizumab, non-steroidal anti-inflammatory drugs (NSAIDs) and steroids)]. Perforations have involved varying regions of the gastrointestinal tract (e.g. stomach, duodenum, colon).
Use Relistor with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with Relistor and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms.

Use in patients with hepatic/renal impairment.

Relistor is not recommended in patients with severe hepatic impairment or with end-stage renal impairment requiring dialysis.

Patients with other conditions.

Use of methylnaltrexone bromide in patients with colostomy, peritoneal catheter, active diverticular disease or faecal impaction has not been studied. Therefore, Relistor should only be administered with caution in these patients. Relistor should not be used in patients with known or suspected mechanical bowel obstruction.
Relistor is not recommended for use in post-operative ileus, including patients who have undergone gastrointestinal resection.
Abdominal cramping or abdominal pain are common following treatment with Relistor. Patients given Relistor who develop severe or persistent abdominal pain that is not relieved by laxation should discontinue treatment and be evaluated by their physician.

Use in the elderly.

In the phase 2 and 3 double-blind studies, a total of 77 patients aged 65-74 years (54 methylnaltrexone, 23 placebo) and a total of 100 patients aged 75 years or older (61 methylnaltrexone, 39 placebo) were enrolled. There was no difference in the efficacy or safety profile of these elderly patients when compared to younger patients. Therefore, no dose adjustment is recommended based on age.

Paediatric use.

Safety and efficacy of Relistor have not been established in paediatric patients.

Effects on laboratory tests.

No data available.

Effect on cardiac repolarization.

In a double blind, randomised, parallel-group ECG study of single, subcutaneous doses of methylnaltrexone (0.15, 0.30 and 0.50 mg/kg), in 207 healthy volunteers, no signal of QT/QTc prolongation or any evidence of an effect on secondary ECG parameters or waveform morphology was detected as compared to placebo and a positive control (orally administered 400 mg moxifloxacin).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs metabolised by cytochrome P450 isozymes.

Methylnaltrexone does not affect the pharmacokinetics of drugs metabolized by cytochrome P450 (CYP) isozymes. Methylnaltrexone is minimally metabolised by CYP isozymes. In vitro drug metabolism studies suggest that methylnaltrexone does not inhibit the activity of CYP1A2, CYP2A6, CYP2C9, CYP2C19 or CYP3A4, while it is a weak inhibitor of the metabolism of a model CYP2D6 substrate. In a clinical drug interaction study in healthy adult male subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

Abuse and dependence.

Relistor is a peripherally acting mu-opioid receptor antagonist with no known risk of abuse and/or dependence.

Onset of action.

Data from clinical trials demonstrated that Relistor may induce rapid onset (within 30 minutes) of a bowel movement (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients should therefore, be advised to remain close to toileting facilities after each dose.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Subcutaneous treatment of rats with methylnaltrexone at a dose (25 mg/kg/day) resulting in estimated exposures (based on AUC) that were 36 times clinical exposure had no effect on fertility. Slightly decreased fertility was observed with a subcutaneous dose of 150 mg/kg/day.
(Category B1)
There are no adequate and well-controlled studies in pregnant women using methylnaltrexone bromide. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. The potential for teratogenic effects of Relistor on the human foetus is unknown. Reproduction studies have been performed in pregnant rats and rabbits. There were no effects on foetal development at intravenous doses of up to 25 mg/kg/day in the rat or up to 16 mg/kg/day in the rabbit, which resulted in respective drug exposures (AUC) of 165 and 82 times that expected in humans treated with the normal therapeutic dose.

Labour and delivery.

Methylnaltrexone at subcutaneous doses of up to 25 mg/kg/day had no effect on labour, delivery and offspring development in rats. This dose resulted in a drug exposure that was 36 times that expected in humans treated with the normal therapeutic dose. Reduced postnatal weight gain of offspring and slightly delayed female sexual maturation were observed at a higher dose (100 mg/kg/day).
It is not known whether Relistor is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Relistor is administered to a nursing woman. Methylnaltrexone and/or its metabolites are excreted in the milk of lactating rats.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive have been performed. However, as a pure peripherally restricted opioid antagonist, the likelihood that methylnaltrexone will affect driving is low. Dizziness may occur, and this may have an effect on driving.

4.8 Adverse Effects (Undesirable Effects)

In the clinical development program 286 patients have received at least one dose of Relistor and 23 patients have received Relistor intermittently for 3 to 4 months. See Table 2.

Clinical trial experience.

The safety of Relistor was evaluated in two, double-blind, placebo-controlled trials in patients receiving palliative care. Study 301 included a single-dose, double-blind, placebo-controlled period, whereas Study 302 included a 14-day multiple-dose, double-blind, placebo-controlled period. In both studies, patients had advanced illness with the majority having 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. Patients were receiving 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). Both the methylnaltrexone and placebo patients were on a stable laxative regimen for at least 3 days prior to study entry and continued on their regimen throughout the study.

Postmarketing experience.

Expected frequency of adverse reactions is presented in CIOMS frequency categories: very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%.

Skin and subcutaneous tissue disorders.

Common: hyperhidrosis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

During clinical trials of Relistor administered subcutaneously, no cases of methylnaltrexone overdose were reported. In a study of healthy volunteers (n = 41), a single dose of 0.50 mg/kg administered as a subcutaneous injection was well tolerated. A study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus.

Management.

In the event of an overdose, signs and symptoms of orthostatic hypotension should be monitored and treatment should be initiated, as appropriate.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Methylnaltrexone is a competitive antagonist of opioid receptor binding with an 8-fold selectivity for the mu-opioid receptor over the kappa-receptor. It does not interact significantly with the delta 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 antagonist in tissues such as the gastrointestinal tract, without impacting opioid-mediated analgesic effects on the central nervous system.

Clinical trials.

The efficacy and safety of Relistor in the treatment of opioid-induced constipation in patients receiving palliative care was demonstrated in two randomised, double-blind, placebo controlled studies. In these studies, the median age was 68 years (range 21-100); 51% were females. In both studies, patients had advanced illness, with the majority having 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 and had a life expectancy of less than 6 months. 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 randomisation (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. Twenty-three patients received Relistor intermittently for a period of 3-4 months. No longer term efficacy information is available.
Study 301 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 (see Figure 1).
Study 302 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 analysed. 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 (see 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, approximately half of those patients who responded to Relistor within 4 hours had a laxation within 30 minutes (see Figures 2, 3). In addition, there was no evidence to suggest 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.

In Study 302 the laxation response rate was consistent from dose 1 through dose 7 over the course of the 2-week, double-blind period of EXT 302.
During the open-label treatment periods in studies 301, 301EXT and 302EXT, the laxation response rates observed were comparable to those seen for active methylnaltrexone (MNTX) during double-blind treatment. Patients used methylnaltrexone (MNTX) as needed with a median of 3.2 days between doses. Laxation rates were generally stable over the course of 3 to 4 months of open label treatment.

Opioid use and pain scores.

There was no significant relationship between baseline opioid dose and laxation response in methylnaltrexone-treated patients in 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 or placebo-treated patients.

5.2 Pharmacokinetic Properties

Absorption.

Methylnaltrexone is absorbed rapidly, with peak concentrations (C_max) achieved at approximately 0.5 hours following subcutaneous administration. Peak plasma concentration and area under the plasma concentration-time curve (AUC) increase in a dose proportional manner. The mean C_max (± SD) values were 117 ± 33 nanogram/mL, 234 ± 65 nanogram/mL and 392 ± 148 nanogram/mL at 0.15 mg/kg, 0.30 mg/kg and 0.50 mg/kg, respectively. The mean AUC values were 180 ± 37 nanogram.h/mL, 376 ± 73 nanogram.h/mL and 593 ± 111 nanogram.h/mL at 0.15 mg/kg, 0.30 mg/kg and 0.50 mg/kg, respectively. Absolute bioavailability of a 0.30 mg/kg subcutaneous dose versus a 0.30 mg/kg intravenous dose is 82%.

Distribution.

Methylnaltrexone undergoes moderate tissue distribution. The steady-state volume of distribution (Vss) is approximately 1.1 L/kg. Methylnaltrexone is minimally bound to human plasma proteins in vitro (about 11.0% at a concentration close to the plasma C_max) as determined by equilibrium dialysis.

Metabolism.

Methylnaltrexone is minimally metabolised in humans. Conversion to methyl-6-naltrexol isomers and methylnaltrexone sulfate appears to be the primary pathway of metabolism. Each of the methyl-6-naltrexol isomers has somewhat less antagonist activity than the parent compound and a low exposure in plasma of approximately 8% of the drug-related materials. Methylnaltrexone sulfate is an inactive metabolite and present in plasma at a level of approximately 25% of drug related materials. N-demethylation of methylnaltrexone to produce naltrexone is not significant (0.06% of the administered dose).

Excretion.

Methylnaltrexone is eliminated primarily as the unchanged drug. Approximately half of the dose is excreted in the urine and somewhat less in faeces. The terminal disposition half-life (t_1/2) is approximately 8 hours.

Elderly.

Paediatric use.

The pharmacokinetics of methylnaltrexone have not been studied in children.

Patients with renal impairment.

In a study of volunteers with varying degrees of renal impairment receiving a single dose of 0.30 mg/kg methylnaltrexone, renal impairment had a marked effect on the renal excretion of methylnaltrexone. The renal clearance of methylnaltrexone decreased with increasing severity of renal impairment. Severe renal impairment decreased the renal clearance of methylnaltrexone by 8 to 9-fold, however, this resulted in only a 2-fold increase in total methylnaltrexone exposure (AUC). C_max was not significantly changed. No studies were performed in patients with end-stage renal impairment requiring dialysis.

Patients with 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 C_max of methylnaltrexone. The effect of severe hepatic impairment on the pharmacokinetics of methylnaltrexone has not been studied.

Effect of bodyweight on exposure to methylnaltrexone.

An integrated analysis of pharmacokinetic data from 137 healthy subjects who received Relistor subcutaneously with the mg/kg dosing adjustment used in studies 301 and 302, indicated that methylnaltrexone exposure (AUC) per unit dose (mg/kg) increased as bodyweight increased. In addition, the analysis showed that equivalent methylnaltrexone exposure to that at 0.15 mg/kg can be achieved with a two weight-band-based dosing adjustment of an 8 mg dose for bodyweight 38 to less than 62 kg or a 12 mg dose for bodyweight 62 to 114 kg.

5.3 Preclinical Safety Data

Genotoxicity.

Methylnaltrexone was not genotoxic in in vitro tests for bacterial gene mutation forward mutation in mammalian cells or chromosome aberrations in Chinese hamster ovary cells and human lymphocytes. There was no evidence of genotoxicity in in vivo mouse micronucleus tests for clastogenicity at exposures of more than 200 times clinical exposure at the maximal recommended dose.

Carcinogenicity.

Carcinogenesis studies have not been conducted with methylnaltrexone.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients are 3.9 mg sodium chloride, 0.24 mg sodium calcium edetate, and 0.18 mg glycine hydrochloride diluted to 0.6 mL with water for injections. During manufacture, the pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Relistor injection should be stored below 30°C. Protect from light. Use as soon as possible after withdrawal into the syringe. Once drawn into the syringe, if immediate administration is not possible, store at room temperature for not more than 6 hours.

6.5 Nature and Contents of Container

Relistor injection is provided in a clear, Type I, flint glass, single use vial with a grey butyl rubber stopper and aluminium overseal with flip-off-cap. The following packs are available:
A single 3 mL vial containing 12 mg of methylnaltrexone bromide.
A convenience pack containing 7 cartons. Each carton contains one vial, one 1 mL syringe and two alcohol swabs.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Chemical name: (R)-N-(cyclopropylmethyl) noroxymorphone methobromide.
Molecular formula: C₂₁H₂₆NO₄Br. Molecular weight: 436.36.

CAS number.

73232-52-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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Relistor

Methylnaltrexone bromide

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