methylthioninium chloride: package leaflet

3 tablets.

If you take more Lumeblue than you should

The box contains one complete dose of Lumeblue. Therefore you cannot take more Lumeblue than you should. However, if you take more tablets than you should, you might get some of the side effects listed in section 4. If you think you have taken more of this medicine than you should, tell your doctor or nurse as soon as possible.

If you notice any of the following symptoms you should tell your doctor straight away:
- Feeling or being sick, or stomach pain
- Abnormally fast beating of the heart, or chest pain
- Tight chest or difficulty breathing (e.g. breathlessness)
- Confusion, dizziness, or headache
- Sweating, tremor, feeling weak, paler skin than usual, or skin turning blue
- An increase in methaemoglobin (an abnormal form of haemoglobin in the blood);
- High blood pressure.

If you forget to take one or more of the doses of Lumeblue

Do not take a double dose to make up for forgotten tablets, take the next dose of tablets according to the bowel cleansing schedule given to you by your doctor, it may be helpful to set an alarm to remind you when to take the medicine.

If you stop taking Lumeblue

At your colonoscopy, tell your doctor that you did not take all the tablets.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects are common, but tell your doctor or nurse if you are worried about any side effect you get:

Very common (may affect more than 1 in 10 people)
- Discoloured urine
- Discoloured faeces
- Dizziness
- Changes in your sense of taste
- Pins and needles sensation, tingling or prickling
- Pain or discomfort in your hands or feet
- Blue discolouration of the skin
- Sweating

Common (may affect up to 1 in 10 people)
- Nausea
- Vomiting
- Stomach or chest pain
- Headache
- Anxiety

Uncommon (may affect up to 1 in 100 people)
- Cold-like symptoms, including blocked or runny nose
- Migraine
- Low blood pressure
- Cough
- Vomiting blood
- Bruising-like discolouration of the skin,
- Night sweats
- Itchy skin
- Rash
- Spidery veins
- Pain in the back or sides
- Abnormally large amounts of urine, or pain or difficulty when passing urine
- General pain
- Chills

Not known (frequency cannot be estimated from the available data)
- Signs of serotonin syndrome, such as muscle spasms, clumsiness, tremors, confusion or other mental changes
- Signs of an anaphylactic reaction, such as itchy rash, throat or tongue swelling, shortness of breath.
- Sensitivity to light

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting

system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the blister after EXP.
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not use this medicine if the pack is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Lumeblue contains
- The active substance is methylthioninium chloride. Each prolonged-release tablet contains 25 mg methylthioninium chloride.
- The other ingredients are:
Tablet core: stearic acid 50 (E570), soya lecithin (E322) – see section 2 under ‘Lumeblue contains soya lecithin’, microcrystalline cellulose (E460), hypromellose 2208 (E464), mannitol (E421), talc (E553b), silica colloidal anhydrous (E551), magnesium stearate (E470b).
Film coating: methacrylic acid–methyl methacrylate copolymer, talc (E553b), titanium dioxide (E171), triethyl citrate (E1505).

What Lumeblue looks like and contents of the pack

Lumeblue prolonged-release tablets are off-white to light blue, round, biconvex, enteric-coated tablets.
The prolonged-release tablets are provided in blister packs containing 8 tablets.

Marketing Authorisation Holder

Cosmo Technologies Ltd
Riverside II
Sir John Rogerson’s Quay
Dublin 2
Ireland

Manufacturer

Cosmo S.p.A
Via C. Colombo, 1
20045, Lainate
Milan,
Italy

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu

Methylthioninium chloride (also called methylene blue) belongs to a group of medicines called antidotes.
Methylthioninium chloride Proveblue will be given to you or your child (0-17 years old) to treat problems with your blood resulting from exposure to some medicines or chemicals that can cause a disease called methaemoglobinaemia.
In methaemoglobinaemia, your blood contains too much methaemoglobin (an abnormal form of haemoglobin that is not able to transport oxygen around your body effectively). This medicine will help your haemoglobin return to normal and restore the transport of oxygen in the blood.

You must not be given Methylthioninium chloride Proveblue
- if you are allergic to methylthioninium chloride or other thiazine dyes
- if your body does not produce enough of the enzyme G6PD (glucose-6-phosphate dehydrogenase)
- if your body does not produce enough of the enzyme NADPH (nicotinamide adenine dinucleotide phosphate) reductase
- if your blood disorder has been caused by nitrite during treatment of cyanide poisoning
- if your blood disorder has been caused by chlorate poisoning.

Warnings and precautions
Talk to your doctor or nurse before you are given Methylthioninium chloride Proveblue
- if you have moderate or severe renal disease; lower single dose (1 to 2 mg/kg maximum) is needed
- if your blood disorder has been caused by a chemical called aniline, which is contained in dyes;
lower doses may be needed and total cumulative dose should not exceed 4 mg/kg (see section 3 of this package leaflet)
- if your blood disorder has been caused by a medicine called dapsone (used to treat leprosy and other skin conditions); lower doses may be needed and total cumulative dose should not exceed 4 mg/kg (see section 3)
- if you suffer from hyperglycaemia or diabetes mellitus, as these conditions may be worsened by the glucose solution used for the dilution of the medicine

• your urine and stools may turn a blue-green colour; and skin may possibly turn a blue colour when you are treated with Methylthioninium chloride Proveblue. This discolouration is expected and will disappear after the treatment has ended If any of the above applies to you, please consult your doctor.

Photosensitivity
Methylthioninium chloride may cause a photosensitivity reaction in the skin (sunburn-like reaction) when exposed to strong light sources, such as light therapy, lights in operating rooms and pulse oximeters.
Protective measures against exposure to light should be taken.

Monitoring tests
You will undergo monitoring tests during and after treatment with Methylthioninium chloride Proveblue.

Children
Special care must be taken with Methylthioninium chloride Proveblue:
- in newborns and infants 3 months old or younger, lower doses are recommended (see section 3 of this package leaflet).

Other medicines and Methylthioninium chloride Proveblue
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
You should not be given methylthioninium chloride at the same time you are taking certain medicines to treat depression or anxiety which affect a brain chemical called serotonin. When used in combination with these medicines methylthioninium chloride may cause serotonin syndrome, which can be potentially life-threatening. Such medicines include:
- Selective serotonin reuptake inhibitors (SSRIs) such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and zimelidine
- bupropion
- buspirone
- clomipramine
- mirtazapine
- venlafaxine
- Monoamine oxidase inhibitors

Opioids, for example, tramadol, fentanyl, pethidine, and dextromethorphan, may also increase the risk of developing serotonin syndrome, when used in combination with methylthioninium chloride.
However, if the intravenous use of methylthioninium chloride cannot be avoided, you should be administered the lowest possible dose and observed closely for up to 4 hours after administration.
If you have any doubts about whether this medicine should be given to you, consult your doctor.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before you are given this medicine.
The use of Methylthioninium chloride Proveblue during pregnancy is not recommended unless it is clearly necessary, for example in a life-threatening situation.
Due to a lack of available data on whether methylthioninium chloride passes into human breast milk, breast-feeding should be discontinued for up to 8 days after treatment with this medicine.

Driving and using machines
Do not drive or use any tools or machines as methylthioninium chloride has moderate influence on the ability to drive and use machines.

Your doctor will inject this medicine into a vein (intravenously) slowly over a period of 5 minutes.

Adults, children above 3 months and elderly
The usual dose is 1 to 2 mg per kilogram of your body weight, i.e. 0.2 to 0.4 ml per kilogram given over a period of 5 minutes. A second dose may be given after one hour if required.
The maximum recommended cumulative dose for the course of treatment is 7 mg/kg.
If your blood disorder has been caused by aniline or dapsone, total cumulative dose should not exceed 4 mg/kg (see section 2).
Usually, treatment should not exceed one day.
Renal Impairment
In infants above 3 months, children and adolescents and in adults, the recommended dosage in patient with moderate renal impairment (eGFR 30-59 ml/min/1.73 m2) is 1-2 mg/kg per body weight. If a 1 mg/kg dose is given, a repeat dose of 1 mg/kg may be given one hour after the first dose in cases of persistent or recurrent symptoms or if methaemoglobin levels remain significantly higher than the normal clinical range. The maximum recommended cumulative dose for the course of treatment is 2 mg/kg.

In infants above 3 months, children and adolescents and in adults, the recommended dosage in patient with severe renal impairment (eGFR 15-29 ml/min/1.73 m2) is a single dose of 1 mg/kg per body weight.
The maximum recommended cumulative dose for the course of treatment is 1 mg/kg.

Methylthioninium chloride should be used with caution in infants 3 months old or younger and newborn infants with moderate to severe renal impairment (eGFR 15-59 ml/min/1.73 m2) since there is no data available and methylthioninium chloride is predominantly renally eliminated. Lower maximum cumulative doses (<0.5 mg/kg body weight) may be considered.

No dose adjustment is recommended in patients with mild renal impairment (eGFR 60-89 ml/min/1.73 m2).

Infants 3 months old or younger
The recommended dose is 0.3 to 0.5 mg/kg body weight, i.e. 0.06 to 0.1 ml/kg, over a period of 5 minutes.
A repeat dose (0.3 to 0.5 mg/kg body weight, i.e. 0.06-0.1 ml/kg) may be given after one hour in case of persistence or recurrence of symptoms. Usually, treatment should not exceed one day.
This medicine may be diluted in 50 ml glucose 50 mg/ml (5%) solution for injection to avoid local pain, in particular in children.

If you are given more Methylthioninium chloride Proveblue than you should
As this medicine will be given to you whilst you are in hospital, it is unlikely that you will be given too much or too little, however, tell your doctor if you notice one of the following adverse reactions:
- feeling sick,
- stomach pain,
- chest pain,
- dizziness,
- headache,
- sweating,

- confusion,
- an increase in methaemoglobin (an abnormal form of haemoglobin in the blood),
- high blood pressure,
- shortness of breath,
- abnormally fast beating of the heart,
- tremor,
- skin discolouration. Your skin may turn blue
- reduction in red blood cells which may turn your skin pale and make you breathless and weak,
- jaundice (yellowing of the skin and eyes), this has only been reported in infants.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, Methylthioninium chloride Proveblue can cause side effects, although not everybody gets them.
These effects are the same in adults and children except jaundice which has only been reported in infants.

• Very common side effects (may affect more than 1 in 10 people)
• pain in extremity
• dizziness
• sweating
• skin discolouration. Your skin may turn blue
• blue or green urine
• numbness and tingling
• abnormal taste in mouth
• nausea

• Common side effects (may affect up to 1 in 10 people):
• stomach pain
• chest pain
• headache
• anxiety
• injection site pain
• vomiting

• Not known (frequency cannot be estimated from the available data):
• serotonin syndrome when Methylthioninium chloride Proveblue has been taken with certain medicines to treat depression or anxiety, see section 2
• decreased haemoglobin (protein in red blood cells that carry oxygen in the blood) levels may be

reported during blood tests
- reduction in red blood cells which may turn your skin pale and make you breathless and weak
- local tissue damage at the injection site
- jaundice (yellowing of the skin and eyes) – this has only been reported in infants
- problems with speech
- high or low blood pressure
- agitation
- lack of oxygen
- irregular heartbeat, including an abnormally slow or fast beating of the heart
- severe allergic reactions (so called anaphylactic reaction which may cause your throat or face to swell, difficulty breathing or a severe rash)
- an increase in methaemoglobin (an abnormal form of haemoglobin in the blood)
- shortness of breath
- confusion
- shaking
- hives
- fever
- rapid breathing
- dilated pupils
- discoloured stools. They may appear green or blue
- increased sensitivity of your skin to light (photosensitivity)

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.
You should not be given this medicine after the expiry date which is printed on the carton and the ampoule labels after EXP. The expiry date refers to the last day of that month. The doctor or nurse will check that the expiry date on the label has not been passed before administering the injection to you.
Do not refrigerate or freeze. Keep the ampoule in the original package in order to protect from light.
The medicine must be used immediately after opening or dilution.
Do not use Methylthioninium chloride Proveblue if the solution is discoloured, cloudy, turbid, or a precipitate or particles are present.
Any unused product or waste material should be disposed of in accordance with local requirements.

What Methylthioninium chloride Proveblue contains
- The active substance is methylthioninium chloride.
Each ml of solution contains 5 mg methylthioninium chloride.
Each 10 ml ampoule contains 50 mg methylthioninium chloride.
Each 2 ml ampoule contains 10 mg methylthioninium chloride.
- The other ingredient is water for injections.

What Methylthioninium chloride Proveblue looks like and contents of the pack
Methylthioninium chloride Proveblue is a clear dark blue solution for injection (injection) and is supplied in clear glass ampoules.
Each box contains a tray with 5 ampoules of 10 ml.
Each box contains a tray with 5 ampoules of 2 ml.
Each box contains a tray with 20 ampoules of 2 ml.

Marketing Authorisation Holder
Provepharm SAS
22 rue Marc Donadille, 13013 Marseille, France

Manufacturer
Cenexi
52, Rue Marcel et Jacques Gaucher, 94120 Fontenay-sous-Bois, France

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
Pharmanovia Benelux B.V.
Tél/Tel: + 31 (0) 76-5600030
Lietuva
Provepharm SAS
Tel: +33 (0)4 91 08 69 30

България
Provepharm SAS
Teл.: + 33 (0)4 91 08 69 30

Luxembourg/Luxemburg
Pharmanovia Benelux B.V.
Tél/Tel: + 31 (0) 76-5600030
Česká republika
LERAM pharmaceuticals s.r.o
Tel: +420 737 657 454
Magyarország
Mediwings Pharma Kft.
Tel.: + 36 28 410 463

Danmark
Pharmanovia A/S
Tlf.: + 45 33 33 76 33

Malta
Provepharm SAS
Tel: + 33 (0)4 91 08 69 30

Deutschland
Dr. Franz Köhler Chemie GmbH
Tel: + 49 (0) 6251-1083-0

Nederland
Pharmanovia Benelux B.V.
Tel: + 31 (0) 76-5600030

Eesti
Provepharm SAS
Tel: + 33 (0)4 91 08 69 30

Norge
Pharmanovia A/S
Tlf: + 45 33 33 76 33

Ελλάδα a VIPharma International AE
Τηλ: + 30-210-6194170

Österreich
Dr. Franz Köhler Chemie GmbH
Tel: + 49 (0) 6251-1083-0

España
Fresenius Kabi España, S.A.U.
Tel: + 34 93 225 65 65

Polska
Apfel Pharm Sp. z o.o.
Tel: + 48 694 775 205

France
Provepharm SAS
Tél: + 33 (0)4 91 08 69 30

Portugal
Labesfal - Laboratórios Almiro
Tel: + 351 232 831100

Hrvatska
Provepharm SAS
Tel: + 33 (0)4 91 08 69 30
România
Provepharm SAS
Tel: + 33 (0)4 91 08 69 30

Ireland
Provepharm SAS
Tel: + 33 (0)4 91 08 69 30

Slovenija
Provepharm SAS
Tel: + 33 (0)4 91 08 69 30

Ísland
Pharmanovia A/S
Sími: + 45 33 33 76 33

Slovenská republika
LERAM pharmaceuticals s.r.o
Tel: +420 737 657 454
Italia
Altais Pharma S.r.l
Tel: +39 06 97 79 70 56

Suomi/Finland
Pharmanovia A/S
Puh/Tel: + 45 33 33 76 33

Κύπρος
Isangen Pharma Cyprus Ltd
Τηλ: + 357-24-638833
Sverige
Pharmanovia A/S
Tel: + 45 33 33 76 33

Latvija
Provepharm SAS
Tel: + 33 (0)4 91 08 69 30

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.

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The following information is intended for healthcare professionals only:

Preparation for intravenous administration

Use immediately on opening. Inject very slowly over a period of 5 minutes.

Methylthioninium chloride Proveblue is hypotonic and may be diluted in 50 ml glucose 50 mg/ml (5%) solution for injection to avoid local pain, in particular in paediatric population.
It must not be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection because it has been demonstrated that chloride reduces the solubility of methylthioninium chloride.

Additional information on how Methylthioninium chloride Proveblue can be given is provided in section 3 of the Package Leaflet.

Any unused product or waste material should be disposed of in accordance with local requirements.