Consumer medicine information

Relistor

Methylnaltrexone bromide

BRAND INFORMATION

Brand name

Relistor

Active ingredient

Methylnaltrexone bromide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Relistor.

SUMMARY CMI

RELISTOR®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using RELISTOR?

RELISTOR contains the active ingredient methylnaltrexone bromide. RELISTOR is used to relieve constipation caused by strong pain relievers called opiates (for example, morphine, codeine).

For more information, see Section 1. Why am I using RELISTOR? in the full CMI.

2. What should I know before I use RELISTOR?

Do not use if you have ever had an allergic reaction to RELISTOR or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use RELISTOR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with RELISTOR and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use RELISTOR?

  • RELISTOR is given by subcutaneous injection in the upper arm, abdomen or thigh as a single dose, on alternate days.
  • RELISTOR is for single use in one patient only.

More instructions can be found in Section 4. How do I use RELISTOR? in the full CMI.

5. What should I know while using RELISTOR?

Things you should do
  • Be near a toilet. A bowel movement may occur quickly, within 30mins after being given RELISTOR.
  • Remind any doctor, dentist or pharmacist you visit that you are using RELISTOR.
  • Tell your doctor if you experience severe or persistent diarrhoea whilst using RELISTOR.
Things you should not do
  • Do not use RELISTOR if you know or suspect there is a blockage of the intestines (mechanical bowel obstruction).
Driving or using machines
  • Be careful driving or operating dangerous machinery until you know how it affects you, as RELISTOR may cause dizziness.
Looking after your medicine
  • RELISTOR should be stored below 30°C, protected from light.
  • Once RELISTOR is drawn into a syringe, use immediately or discard after 6 hours.

For more information, see Section 5. What should I know while using Relistor? in the full CMI.

6. Are there any side effects?

Abdominal cramping or abdominal pain are common, after receiving RELISTOR. However if this pain is not relieved by having a bowel motion, speak to your doctor. If you have severe, persistent and/or worsening abdominal pain, nausea, or vomiting, stop using RELISTOR and tell your doctor.

Side effects that require urgent medical attention include: Signs of an allergic reaction, such as chest tightness, difficulty breathing, swelling of face lips and tongue.

Other possible side effects include: flatulence, nausea, dizziness, diarrhoea, excessive sweating.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

RELISTOR®

Active ingredient(s): methylnaltrexone bromide

Consumer Medicine Information (CMI)

This leaflet provides important information about using RELISTOR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using RELISTOR.

Where to find information in this leaflet:

1. Why am I using RELISTOR?
2. What should I know before I use RELISTOR?
3. What if I am taking other medicines?
4. How do I use RELISTOR?
5. What should I know while using RELISTOR?
6. Are there any side effects?
7. Product details

1. Why am I using RELISTOR?

RELISTOR contains the active ingredient methylnaltrexone bromide. RELISTOR is a type of opioid receptor antagonist, that blocks the effects of opioids in the gastrointestinal tract, without affecting pain relief.

RELISTOR is used to relieve constipation caused by opioid pain relievers.

RELISTOR is used when other medicines used to treat constipation (laxatives) have not worked effectively.

2. What should I know before I use RELISTOR?

Warnings

Do not use RELISTOR if:

  • You are allergic to methylnaltrexone bromide, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • You have or suspect a blockage in the bowel (mechanical bowel obstruction).
  • You have severe, persistent or worsening abdominal pain, nausea or vomiting.

Check with your doctor if you:

  • Take any medicines for any other condition
  • Have any existing bowel related conditions, such as a colostomy, a peritoneal catheter, diverticular disease, or any faecal impaction.
  • Have suffered from constipation before you had to take opioid pain killers
  • Have severe kidney disease. Your doctor may reduce your dose of RELISTOR.
  • You have severe liver disease.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. The effect of RELISTOR on pregnancy is unknown. The use of RELISTOR during pregnancy is therefore not recommended.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is unknown whether RELISTOR passes into human breast milk. The use of RELISTOR whilst breastfeeding is therefore not recommended.

3. What if I am taking other medicines?

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

The following medicines, when used in conjunction with RELISTOR may increase the risk of gastric side effects:

  • Bevacizumab (used to treat some cancers)
  • Non-steroidal anti inflammatory drugs (NSAIDs), used to treat inflammation, pain and fever
  • Steroids (used to treat inflammation)

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect RELISTOR.

4. How do I use RELISTOR?

How much to use

  • Your doctor will determine what dose, and for how long you should be given RELISTOR.
  • RELISTOR is usually given as a single dose on alternate days. The interval between doses may be longer. 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 to use RELISTOR

  • RELISTOR is given by subcutaneous (under the skin) injection in either the upper arm, abdomen or thigh.
    It is recommended to change the site of injection every time the injection is given
  • Do not inject into areas where the skin is tender, bruised, red or hard. Take care to avoid areas with scars or stretch marks.
  • RELISTOR may be injected without regard to food.
  • RELISTOR is for single use, in one patient only.
    Discard any residue.
  • Only use RELISTOR if the solution is clear, colourless to pale yellow, and does not contain lumps or flakes or particles.

If you forget to use RELISTOR

If you miss a dose of RELISTOR, you should contact your doctor or pharmacist as soon as possible.

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

If you use too much RELISTOR

If you think that you have used too much RELISTOR, you may need urgent medical attention.

Be careful when standing up, as your blood pressure may be affected. If sitting or lying down, stand up slowly.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26 in Australia), or (by calling 0800 764 766 in New Zealand)
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using RELISTOR?

Things you should do

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

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 very quickly, within 30 minutes after injection of the medicine.

Remind any doctor, dentist or pharmacist you visit that you are using RELISTOR.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how RELISTOR affects you.

RELISTOR may cause dizziness in some people

Looking after your medicine

  • Store below 30°C.
  • Protect from light.
  • Use as soon as possible after opening and withdrawal into the syringe. If immediate use is not possible, store at room temperature, and discard after 6 hours.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal side effects:
  • Abdominal pain
  • Flatulence
  • Nausea
  • Diarrhoea
Other:
  • Dizziness
  • Excessive sweating
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • New, persistent or worsening abdominal pain, nausea, or vomiting
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What RELISTOR contains

Active ingredient
(main ingredient)		Methylnaltrexone bromide
Other ingredients
(inactive ingredients)		Glycine hydrochloride
Hydrochloride acid
Sodium calcium edetate
Sodium chloride
Sodium hydroxide
Water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What RELISTOR looks like

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

(Aust R 144062).

Who distributes RELISTOR

Link Medical Products Pty Ltd
5 Apollo Street
Warriewood, NSW 2102
Australia
Ph: 1800 181 060
linkhealthcare.com.au

Link Pharmaceuticals Ltd
Suite 32, Level 26,
188 Quay Street
Auckland 1010
New Zealand
Ph: +64(9) 358 7146

This leaflet was prepared in September 2021.

Published by MIMS December 2021

BRAND INFORMATION

Brand name

Relistor

Active ingredient

Methylnaltrexone bromide

Schedule

S4

 

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 (Cmax) 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 Cmax (± 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 Cmax) 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 (t1/2) is approximately 8 hours.

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.

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). Cmax 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 Cmax 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.

Summary Table of Changes