SUMMARY CMI

PROVEBLUE^®

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 PROVEBLUE?

PROVEBLUE contains the active ingredient methylene blue. PROVEBLUE is used to treat abnormal blood pigment levels. These abnormal blood pigments do not carry oxygen properly.

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

2. What should I know before I use PROVEBLUE?

Do not use if you have ever had an allergic reaction to methylene blue, any other dyes, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if your blood disorder has been caused by cyanide or chlorate poisoning, 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 PROVEBLUE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PROVEBLUE 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 PROVEBLUE?

• PROVEBLUE must only be given by a doctor or nurse
• Your doctor will decide what dose of PROVEBLUE you will receive and how long you will receive it

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

5. What should I know while using PROVEBLUE?

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

6. Are there any side effects?

PROVEBLUE will cause a blue colour in your urine or bowel motions. Common less serious side effects include: nausea, vomiting, diarrhoea, headaches, dizziness, redness or swelling at the injection site, change in the colour of your skin, saliva, urine and/or faeces, tingling or numbness of the hands or feet, increased sensitivity to the sun or light. You may need urgent medical attention if you experience any of the following: chest pain, fast or irregular heartbeat, have problems with speaking, writing or reading, have signs of allergic reaction, signs of low blood pressure, signs of anaemia, yellowing of the skin and/or eyes (also called jaundice). This is not a full list of side effects. 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

PROVEBLUE^®

Active ingredient(s): methylene blue

Consumer Medicine Information (CMI)

This leaflet provides important information about using PROVEBLUE. 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 PROVEBLUE.

Where to find information in this leaflet:

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

1. Why am I using PROVEBLUE?

PROVEBLUE contains the active ingredient methylene blue. PROVEBLUE belongs to a group of medicines called dyes.

PROVEBLUE is used to treat abnormal blood pigment levels. These abnormal blood pigments do not carry oxygen properly.

PROVEBLUE is also used:

• To stain bacteria to make them easier to see
• As a visible dye to help in the diagnosis of a number of conditions
• As a stain to dye certain body tissues during surgery

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

2. What should I know before I use PROVEBLUE?

Warnings

Do not use PROVEBLUE if:

• Your blood disorder has been caused by cyanide
• Your blood disorder has been caused by chlorate poisoning
• You are allergic to methylene blue, or any of the ingredients listed at the end of this leaflet
• You are allergic to any other dyes
• Always check the ingredients to make sure you can use this medicine
• You have glucose-6-phosphate dehydrogenase deficiency. This is an inherited condition
• You have or have had severe kidney problems

Check with your doctor if you:

• Have any other medical conditions, such as:
  - kidney problems
  - diabetes. PROVEBLUE may need to be diluted with glucose solution. The amount of glucose may affect your blood glucose levels
• Take any medicines for any other condition
• Have allergies to any other medicines, foods, preservatives or dyes
• Have been given PROVEBLUE before. Tell them how long it was given for
• Have aniline poisoning

PROVEBLUE is not recommended for long-term use.

The use of methylene blue in infants under 4 months of age is not recommended. Your doctor will discuss use of this medicine in infants younger than 4 months if needed.

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.

You should not be given this medicine if you are pregnant or plan to become pregnant.

It may affect your developing baby if you are given PROVEBLUE during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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.

Some medicines may interfere with PROVEBLUE and affect how it works. These include:

• Medicines used to treat depression known as serotonin reuptake inhibitors (SRIs) such as fluoxetine, sertraline and paroxetine and others such as fluvoxamine, escitalopram and citalopram, and serotonin and noradrenaline reuptake inhibitors (SNRIs) like clomipramine, venlafaxine, duloxetine and sibutramine, and monoamine oxydase inhibitors (MAOIs). When used in combination with these medicines PROVEBLUE may cause serotonin syndrome, which can be potentially life-threatening
• Opioids, such as, tramadol, pethidine, and dextromethorphan. When used in combination with these medicines PROVEBLUE may cause serotonin syndrome, which can be potentially life-threatening
• Dapsone - a medicine used to treat bacterial infections

These medicines may be affected by PROVEBLUE or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

4. How do I use PROVEBLUE?

How much is given

• Your doctor will decide what dose of PROVEBLUE you will receive
• This depends on your medical condition and other factors such as your weight
• Sometimes only a single dose of PROVEBLUE is required

When PROVEBLUE is given

• Your doctor will decide when and for how long you will receive PROVEBLUE

How PROVEBLUE is given

• PROVEBLUE must only be given by a doctor or nurse
• PROVEBLUE can be given in two ways depending upon what it is being used for. It can be given:
  - As an injection into a vein either diluted or undiluted, or
  - By mouth after dilution

If you forget to use PROVEBLUE

PROVEBLUE should be given when you are told to by your doctor or nurse. If you miss the appointment for your dose, speak with your doctor or nurse.

If you are given too much PROVEBLUE

As PROVEBLUE is always given to you in a hospital under the supervision of a doctor, it is unlikely that you will receive an overdose.

Symptoms of an overdose are the same as side effects but may be more severe. The symptoms of a side effect are listed under section 6. Are there any side effects?

If you think that you have been given too much PROVEBLUE, you may need urgent medical attention.

You should immediately:

• phone the Poisons Information Centre
  (by calling 13 11 26), or
• 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 PROVEBLUE?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you have been given PROVEBLUE.

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

If you are about to have any blood tests, tell your doctor that you have been given this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Get up slowly if you feel light-headed, dizzy or faint when getting out of bed or standing up. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Call your doctor straight away if you:

• Become pregnant while being given this medicine
• Notice the PROVEBLUE solution is discoloured, cloudy, or contains solids or particles. The solution is normally a clear, blue liquid
• Notice that when mixed with another solution, PROVEBLUE becomes discoloured, cloudy, or has visible solids or particles. The doctor or nurse will check to ensure the medicine is not past its expiry date and has not been tampered with.

Light exposure

• PROVEBLUE can cause a photosensitivity reaction in the skin (sunburn-like reaction) when exposed to strong light sources, such as lights in operating rooms
• Protective measures against light exposure should be taken

Driving or using machines

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

PROVEBLUE may cause dizziness in some people. If you feel dizzy do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

• PROVEBLUE Injection will be stored in the surgery, pharmacy or ward of a hospital
• The injection is kept in a cool, dry place where the temperature is below 25°C

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.

PROVEBLUE will cause a blue colour in urine or bowel motions.

Less serious side effects

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.

Some of these side effects (for example, changes in blood pressure) can only be found when your doctor does tests from time to time to check your progress.

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 PROVEBLUE contains

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

What PROVEBLUE looks like

PROVEBLUE is a clear, dark blue solution in a clear glass ampoule. It is available in a pack of 5 ampoules (Aust R 224639).

Who distributes PROVEBLUE

PROVEBLUE is sponsored in Australia and New Zealand for Provepharm SAS by:

Clinect Pty Ltd
120 - 132 Atlantic Drive
Keysborough VIC 3173
Australia

Free Call Australia:
1800 899 005

Free Call New Zealand:
0800 138 803

This leaflet was prepared in August 2022.

Published by MIMS December 2022

1 Name of Medicine

Methylene blue (also known as methylthioninium chloride).

2 Qualitative and Quantitative Composition

Proveblue injection is a sterile solution containing 50 mg methylene blue trihydrate (equivalent to 42.77 mg of methylene blue anhydrous) in water for injections to 10 mL. The pH of the solution ranges between 3.0 and 4.5.
Methylene blue is a dark blue, crystalline powder with a copper-coloured sheen, or green crystals with a bronze-coloured sheen. It is slightly soluble in water and slightly soluble in ethanol.

3 Pharmaceutical Form

Proveblue is a clear blue solution and contains methylene blue trihydrate 50 mg/10 mL.

4 Clinical Particulars

4.1 Therapeutic Indications

Proveblue is indicated:
for the treatment of drug-induced methaemoglobinaemia;
for the treatment of idiopathic methaemoglobinaemia (in which structural abnormality of haemoglobin is not present);
as a bacteriological stain;
as a dye in diagnostic procedures such as fistula detection;
for the delineation of certain body tissues during surgery.

4.2 Dose and Method of Administration

Dosage.

Adults and children.

4.3 Contraindications

Proveblue is contraindicated in the following circumstances:
known hypersensitivity to the drug or any other thiazide dyes;
patients with severe renal impairment;
patients with glucose-6-phosphate dehydrogenase deficiency;
methaemoglobinaemia due to chlorate poisoning;
methaemoglobinaemia during treatment of cyanide poisoning.
Intrathecal and subcutaneous injection of methylene blue are also contraindicated as they can result in neural damage (intrathecal administration) and necrotic abscess (subcutaneous administration).

4.4 Special Warnings and Precautions for Use

Long term administration of methylene blue may result in marked anaemia due to accelerated destruction of erythrocytes; haemoglobin concentrations should be checked frequently.
If methylene blue is injected subcutaneously or if extravasation occurs, necrotic abscesses may occur (see Section 4.3). Slow injection rates are recommended to prevent high local concentration of the compound.
Methylene blue imparts a blue-green colour to urine, faeces and a blue colour to skin which may hinder a diagnosis of cyanosis.
Caution should be exercised in the course of treating aniline-induced methaemoglobinaemia. The repeated doses, that may be required, may exacerbate Heinz body formation and haemolytic anaemia. Lower doses should be considered.
Exacerbation of dapsone-induced haemolytic anaemia has been reported as a result of the formation of the dapsone reactive metabolite hydroxylamine which oxidises haemoglobin. It is recommended not to exceed a cumulative dose for the course of treatment of 4 mg/kg in patients with dapsone-induced methaemoglobinaemia.
Anaesthesiologists should be vigilant for methaemoglobinaemia in patients receiving dapsone therapy and for BIS (Bispectral Index) interference.
Due to the potential risk of cardiac arrhythmia and hypotension, electrocardiographs (ECG) and blood pressure monitoring is recommended.
Failure to respond to methylene blue suggests cytochrome b₅ reductase deficiency, glucose-6-phosphate dehydrogenase deficiency or sulfhaemoglobinemia. Alternative treatment options should be considered.

Patients with hyperglycaemia or diabetes mellitus.

Patient monitoring.

Methylene blue is a potent monoamine oxidase inhibitor.

Photosensitivity.

Use in renal impairment.

Paediatric use.

Effects on laboratory tests.

Phenolsulfonphthalein excretion test.

Pulse oximetry.

Bispectral index (BIS).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Methylene blue is an in vitro inhibitor of CYP450 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. The clinical consequences of increased plasma concentration of co-administered drugs which are sensitive CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A substrates cannot be ruled out. Methylene blue is an in vitro inducer of CYP1A2. The clinical consequence is not known.
The administration of methylene blue has the potential to transiently increase or decrease the clearance of drugs that are primarily metabolised by these enzymes. The clinical consequences are however considered minimal since methylene blue is used often only once and in an acute emergency setting.
Methylene blue is a potent inhibitor of the transporters OCT2, MATE1 and MATE2-K. The clinical consequences of the inhibition are not known. The administration of methylene blue has the potential to transiently increase the exposure of drugs primarily cleared by renal transport involving the OCT2/MATE pathway, including cimetidine, metformin and acyclovir.
Methylene blue is a substrate of P-glycoprotein (P-gp). The clinical consequences are considered likely to be minimal due to the transient and single dose use that normally occurs in the emergency setting.

Serotonin reuptake inhibitor.

Serotonin syndrome.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

4.7 Effects on Ability to Drive and Use Machines

Driving can be affected due to confusional state, dizziness and possibly eye disturbances. However, the risk is limited as the medical product is intended for acute administration only in emergency situations at hospital.

4.8 Adverse Effects (Undesirable Effects)

The most commonly reported adverse reactions observed during clinical trials following intravenous administration are dizziness, paresthesia, dysgeusia, nausea, skin discoloration, chromaturia, sweating, injection site pain and pain in extremity.
The adverse effects listed in Table 1 occur in adults, children and adolescents (age 0 to 17 years old) after intravenous administration. The frequencies are not known (cannot be estimated from the available data). When indicated, the frequency is based on a very small sample size.
Oral administration may cause gastrointestinal disturbances and dysuria.
Use of methylene blue for endoscopic tattoo has been associated with vascular necrosis, mucosal ulceration, mural necrosis, extramural fat necrosis and inflammatory changes in the colon.
Injection of methylene blue into joint space has resulted in effusion in the treated joint.
Hyperbilirubinaemia has been reported in infants only.

Reporting suspected adverse reactions.

4.9 Overdose

Symptoms.

Individuals with methaemoglobinaemia.

Individuals without methaemoglobinaemia.

Paediatric population.

Treatment of overdosage.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Clinical trials.

5.2 Pharmacokinetic Properties

Absorption.

Distribution.

Metabolism.

Excretion.

5.3 Preclinical Safety Data

Genotoxicity.

Carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injections.

6.2 Incompatibilities

Precipitation has been reported in cases where methylene blue has been diluted with sodium chloride 0.9%, saline (due to presence of chloride ions which have been shown to reduce the solubility of methylene blue).
Methylene blue is reported to be incompatible with caustic alkalis, iodides and dichromates, and oxidising and reducing substances.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light. Do not refrigerate or freeze.

6.5 Nature and Contents of Container

10 mL clear glass ampoule. It is presented as a pack of 5 ampoules.

6.6 Special Precautions for Disposal

Each ampoule is for single use in one patient only. Discard any residue.

6.7 Physicochemical Properties

Chemical Name: 3,7-Bis (dimethylamino) phenothiazin-5-ylium trihydrate.

Chemical structure.

CAS number.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes