Consumer medicine information

Proveblue

Methylene blue trihydrate

BRAND INFORMATION

Brand name

Proveblue

Active ingredient

Methylene blue trihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Proveblue.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you being given PROVEBLUE against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor.

Keep this leaflet in a safe place. You may need to read it again.

What PROVEBLUE is used for

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

This medicine belongs to a group of medicines called dyes.

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.

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.

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

Before you are given PROVEBLUE

When you must not be given it

  • if your blood disorder has been caused by cyanide
  • if your blood disorder has been caused by chlorate poisoning

You should not be given PROVEBLUE if you have an allergy to:

  • any medicine containing methylene blue
  • any other dyes

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

You should not be given this medicine if you have glucose-6-phosphate dehydrogenase deficiency. This is an inherited condition.

You should not be given this medicine if you have or have had severe kidney problems.

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.

You should not be given PROVEBLUE if the solution is discoloured, cloudy, turbid, or a precipitate is present. The solution is normally a clear, blue liquid.

You should not be given this medicine if when diluted with another solution it causes the solution to precipitate, become cloudy, turbid, discolour, or particles are visible.

The doctor or nurse will check to ensure the medicine is not past its expiry date and has not been tampered with.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had kidney problems.

Tell your doctor if you have been given PROVEBLUE before and for how long.

Tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are a diabetic. PROVEBLUE may need to be diluted with glucose solution. The amount of glucose may affect your blood glucose levels.

Tell your doctor if you have aniline poisoning.

If you have not told your doctor about any of the above, tell them before you are given PROVEBLUE.

Taking other medicines

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

Some medicines and PROVEBLUE may interfere with each other. 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
  • 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.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while being given this medicine.

How PROVEBLUE is given

PROVEBLUE must only be given by a doctor or nurse.

How it is given

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
  • by mouth after dilution

How much is given

Your doctor will decide what dose of PROVEBLUE you will receive and how long you will receive it.

This depends on your medical condition and other factors such as your weight.

Sometimes only a single dose of PROVEBLUE is required.

If you are given too much (overdose)

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 Side effects below.

If you notice any symptoms of an overdose immediately contact your doctor or go to the Emergency Department at the nearest hospital.

Contact the Poisons Information Centre on 13 11 26 for further advice on overdose management.

While you are being given PROVEBLUE

Things you must do

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

Tell any other doctors, dentists, and pharmacists who treat you that you have been given this medicine.

If you become pregnant while being given this medicine, tell you doctor immediately.

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.

Things to be careful of

Be careful driving or operating machinery until you know how PROVEBLUE affects you. This medicine may cause dizziness in some people. If you feel dizzy do not drive, operate machinery or do anything else that could be dangerous.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. 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.

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.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given PROVEBLUE.

This medicine helps most people but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

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

Tell your doctor or nurse if you notice any of the following and they worry you:

  • nausea, vomiting, diarrhoea
  • headaches, dizziness
  • mental confusion, anxiety, agitation
  • tremor
  • redness or swelling at the injection site
  • change in the colour of your skin, saliva, urine and/or faeces to blue or blue/green
  • dilated pupils (increase in the size of the black part of the eyes)
  • pain when passing urine
  • tingling or numbness of the hands or feet
  • taste disturbance or loss of taste
  • increased sensitivity to the sun or light

If any of the following happen, tell your doctor immediately or go to the Emergency Department at your nearest hospital:

  • stomach pain
  • chest pain
  • fast or irregular heartbeat
  • pain at the injection site
  • pain in extremities
  • high temperature
  • sweating more than normal
  • low blood pressure signs of which may include loss of consciousness, sever fatigue, feeling lightheaded, buzzing or ringing in the ear and blurring or loss of vision
  • signs of anaemia such as tiredness and shortness of breath when exercising and/or dizziness or pale appearance
  • rash or hives
  • yellow colouring to the skin and/ or eyes; also called jaundice (this has only been reported in infants)
  • having problems with speaking, writing or reading
  • allergic reaction signs of which may include: shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or nurse if you notice anything that is making you feel unwell.

Other side effects not listed above may also 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.

After being given PROVEBLUE

Storage

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.

Product description

What it looks like

PROVEBLUE is a clear, dark blue solution in a clear glass ampoule.

It is available in a pack of 5 ampoules.

Ingredients

Active ingredients:
The active substance is methylene blue. One 10 mL ampoule contains 50 mg methylene blue.

Inactive ingredients:
Water for injections

Sponsor

PROVEBLUE is sponsored in Australia for Provepharm SAS by:

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

Telephone: 1800 899 005

Date of Preparation

This leaflet was prepared in September 2019.

Australian Register Number(s)
AUST R 224639

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Proveblue

Active ingredient

Methylene blue trihydrate

Schedule

S4

 

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.

Proveblue may be administered orally or by intravenous (IV) injection.
In the treatment of acute methaemoglobinaemia, the IV route of administration is usually preferred because it provides a more rapid onset of effect.

Adults and children.

In the treatment of methaemoglobinaemia, methylene blue is administered intravenously as the 0.5% solution in doses of 1 to 2 mg per kg bodyweight injected over a period of 5 minutes. A repeat dose may be given after one hour if required. A maximum dose of 7 mg/kg bodyweight is recommended. The use of methylene blue is not recommended in infants under 4 months of age.
A dose of 5 mg/kg diluted in 500 mL of glucose 5% infused over 1 hour has been used successfully to stain and identify the parathyroid glands.
Proveblue should not be diluted with sodium chloride 0.9% (saline) as precipitation may occur (due to presence of chloride ions which have been shown to reduce the solubility of methylene blue).
A suitable dilution for oral dosing would be 10-20 mL of the 0.5% solution diluted to 100-200 mL with water for injections. The high volume is suggested to reduce the degree of gastrointestinal disturbances and dysuria. The dosage of methylene blue should be calculated on the basis of lean bodyweight.
Use immediately following dilution.
The Proveblue ampoules should be inspected visually prior to administration. The product should not be used if the solution is discoloured, cloudy, turbid or if a precipitate or particles are present.
Each ampoule is for single use in one patient only. Discard any residue. Proveblue contains no antimicrobial agents.

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.

If diluted in glucose 5% (50 mg/mL) solution for injection, Methylene Blue Injection must be used with caution in patients with hyperglycaemia or diabetes mellitus, as these conditions may be exacerbated by the glucose solution.

Patient monitoring.

Full blood count, including reticulocyte count should be undertaken to ensure haemolysis has not occurred. Electrocardiograph (ECG) and blood pressure should be monitored during and after treatment with methylene blue as hypotension and cardiac arrhythmia are potential adverse effects.
Long term administration of methylene blue may result in anaemia. Haemoglobin levels should be monitored during long term therapy.
Methaemoglobin levels should be monitored throughout therapy.

Methylene blue is a potent monoamine oxidase inhibitor.

Methylene blue has recently been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause serious or fatal serotonin toxicity (serotoninergic syndrome) when combined with serotonergic drugs. (1) Avoid concomitant use of methylthioninium chloride with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors. If methylene blue is judged to be indicated serotonin reuptake inhibitors (SRIs) must be ceased, prior to treatment/ procedure/ surgery (see Section 4.5).
Patients treated with methylene blue in combination with serotonergic drugs should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of methylene blue, and initiate supportive treatment.

Photosensitivity.

Methylene blue may cause a cutaneous photosensitivity reaction when exposed to strong light sources, such as phototherapy, those found in operating theatres or locally from illuminating devices such as pulse oximeters.
Advise patients to take protective measures against exposure to light, because photosensitivity may occur after administration of methylene blue.

Use in renal impairment.

Methylene blue is excreted mainly via the urine, primarily as leucomethylene blue. Methylene blue is contraindicated in patients with severe renal impairment. Caution should be exercised when administering methylene blue to patients with mild to moderate renal impairment.

Paediatric use.

Safety and efficacy of methylene blue in infants have not been established. It has been reported that the metabolism of methylene blue to leucomethylene blue is likely to be less efficient in neonates, due to reduced efficiency of NADPH-diaphorase in this age group. The use of methylene blue in infants up to 4 months of age is not recommended.
Extreme caution should be exercised when administering to the newborns and infants below the age of 3 months due to lower concentrations of NADPH-methaemoglobin reductase necessary for reducing methaemoglobin to haemoglobin, making these infants more susceptible to methaemoglobinaemia produced by high doses of methylene blue.

Effects on laboratory tests.

Phenolsulfonphthalein excretion test.

Methylene blue may cause false positive test results.

Pulse oximetry.

Methylene blue may result in an underestimation of the oxygen saturation reading. It is advisable to check the oxygen saturation by cooximetry when available since pulse oximetry may provide a false estimation of oxygen saturation during administration of methylene blue.

Bispectral index (BIS).

Methylene blue may interfere with BIS values.

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.

Methylene blue may interact with any drug that acts as a serotonin reuptake inhibitor (SRI) including, amongst others, selective serotonin reuptake inhibits (SSRIs) such as fluvoxamine, fluoxetine, paroxetine, sertraline, escitalopram and citalopram, serotonin and noradrenaline reuptake inhibitors (SNRIs) like clomipramine, venlafaxine, duloxetine and sibutramine; such combinations have the consequence of potential serious CNS reactions, including potentially fatal serotonin toxicity (serotonin syndrome). Methylene blue should not be coadministered with any drug that acts an SRI. (See Section 4.4.)

Serotonin syndrome.

Spontaneous reports of serotonin syndrome associated with the co-administration of methylene blue and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported. Coadministration of methylene blue and serotonergic agents is therefore not recommended except where administration of methylene blue and concomitant serotonergic agents is essential. In those cases the lowest possible dose should be used and patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia, clonus and incoordination. If signs or symptoms occur physicians should consider discontinuing either one or both agents; if the concomitant serotonergic agent is withdrawn, discontinuation symptoms can occur. Opioids, for example, tramadol, pethidine, and dextromethorphan, may also increase the risk of developing serotonin syndrome when used in combination with methylene blue.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In vitro methylene blue has been shown to reduce motility of human sperm. It has also been shown to inhibit the growth of cultured two-cell mouse embryos and the production of progesterone in cultured human luteal cells. In vivo effects on fertility and reproduction are not known.
(Category D)
Methylene Blue Injection caused ileal abnormalities including foetal intestinal atresia.
Category D. Proveblue should not be administered to pregnant women.
Category D, Australian definition: Drugs which have caused, are suspected to have caused, or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying references should be consulted for further details.
 There is no information on whether or not methylene blue crosses into breast milk. Safety in the newborn has not been established, and hence, it is recommended that breastfeeding is discontinued prior to administration of Proveblue.

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.

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 https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

No specific information is available. However, large doses of methylene blue can produce methaemoglobinaemia. Side effects seen with high doses include chest pain, dyspnoea, restlessness, apprehension, tremors and a sense of oppression. Large doses are irritant to the urinary tract. In addition it can produce a mild haemolysis with moderate hyperbilirubinaemia, reticulosis and slight anaemia. Rarely, however, severe haemolytic anaemia with Heinz body formation has resulted. Methylene blue in large doses could cause a blue discolouration of the skin after methaemoglobin levels have returned to normal.

Individuals with methaemoglobinaemia.

Cumulative doses of methylene blue may lead to dyspnoea and tachypnoea, presumably related to reduced oxygen availability caused by methaemoglobinaemia, chest pain, tremor, cyanosis and haemolytic anaemia.
Haemolytic anaemia has also been reported in case of severe overdose (20-30 mg/kg) in infants and adults with methaemoglobinaemia caused by aniline or chlorates. Haemodialysis may be used in patients with severe haemolysis.

Individuals without methaemoglobinaemia.

The administration of large intravenous doses (≥ 7 mg/kg) of methylene blue to individuals without methaemoglobinaemia induces nausea and vomiting, chest tightness, chest pain, tachycardia, apprehension, severe sweating, tremor, mydriasis, blue-green staining of the urine, blue staining of the skin and mucous membranes, abdominal pain, dizziness, paraesthesia, headache, confusion, hypertension, mild methaemoglobinaemia (up to 7%) and electrocardiogram changes (T wave flattening or inversion). These features resolve generally within 2-12 hours of the injection.

Paediatric population.

Hyperbilirubinaemia has been observed in infants after administration of 20 mg/kg methylene blue.
Death occurred in 2 infants after administration of 20 mg/kg methylene blue. Both infants had complex medical circumstances and methylene blue was only partially responsible.

Treatment of overdosage.

There is no specific antidote for methylene blue overdose. Treatment is symptomatic and supportive. In severe and refractory cases of methaemoglobinaemia, blood transfusions and even exchange transfusions and (possibly) hyperbaric oxygen may be the only alternative available.
For information on the management of overdose contact the Poisons Information Centre: 13 11 26 (Australia). If you are in New Zealand, please call 0800 POISON or 0800 764766.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

In patients with methaemoglobinaemia, therapeutic doses of methylene blue can lower the levels of methaemoglobin in red blood cells. It activates a normally dormant reductase enzyme system that reduces the methylene blue to leucomethylene blue, which is then able to reduce methaemoglobin to haemoglobin. However, in large doses, methylene blue can itself produce methaemoglobinaemia and the methaemoglobin concentration should therefore be closely monitored during treatment. Methylene blue is not effective for the treatment of methaemoglobinaemia in patients with glucose-6-phosphate dehydrogenase deficiency as these patients have a diminished capacity to reduce methylene blue to leucomethylene blue. It is also potentially harmful as patients with glucose-6-phosphate dehydrogenase deficiency are particularly susceptible to the haemolytic anaemia induced by methylene blue.
Methylene blue also possesses weak antiseptic and bacteriological staining properties and is reported to inhibit amine oxidase in tissues. The drug appears to bind irreversibly to viral nucleic acid and cause disruption of the virus molecule upon exposure to light.
The use of methylene blue as a diagnostic aid is based on its ability to stain tissue. Any skin discolouration can be removed with hypochlorite solution.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

No data available.

Distribution.

No data available.

Metabolism.

In tissues, methylene blue is rapidly reduced to leucomethylene blue, which is stabilised as an undetermined salt, complex, or combination form in the urine but not in the blood.

Excretion.

About 75% of an oral dose of methylene blue is excreted in the urine, a small proportion of which is the unchanged drug, while some is excreted via the bile.

5.3 Preclinical Safety Data

Genotoxicity.

Methylene blue was positive to gene mutation assays in bacteria and mouse lymphoma cells, but was negative in the in vivo mouse micronucleus test.

Carcinogenicity.

There is no information on the carcinogenic potential of methylene blue.

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.

The molecular weight of methylene blue trihydrate is 373.9. The molecular formula of hydrated methylene blue is C16H18ClN3S, xH2O (where x=3, 4 or 5) and its structure is as follows:

CAS number.

CAS registry number of methylene blue trihydrate is 7220-79-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes