Methylthioninium chloride Proveblue 5 mg/ml solution for injection

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Methylene blue chloride Proveblue 5 mg/ml solution for injection

methylene blue chloride

Read all of this leaflet carefully before you are given this medicine, because it contains important information for you.

• Keep this leaflet; you may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse, even if it is a side effect not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What Cloruro de metiltionio Proveblue is and what it is used for
2. What you need to know before receiving Cloruro de metiltionio Proveblue
3. How Cloruro de metiltionio Proveblue is administered
4. Possible side effects
5. How to store Cloruro de metiltionio Proveblue
6. Contents of the pack and other information

1. What Cloruro de metiltionio Proveblue is and what it is used for

Methylthioninium chloride (also known as methylene blue) belongs to a group of medicines called antidotes.

Cloruro de metiltionio Proveblue will be administered to you or your child (0–17 years of age) to treat blood disorders caused by exposure to certain medications or chemicals that can lead to a condition called methemoglobinemia.

In methemoglobinemia, the blood contains an excessive amount of methemoglobin (an abnormal form of hemoglobin that is unable to effectively carry oxygen throughout the body).

This medicine will help normalize hemoglobin and restore oxygen transport in the blood.

2. What you need to know before receiving Methylthioninium Chloride Proveblue

Do not receive Methylthioninium Chloride Proveblue

• if you are allergic to methylthioninium chloride or to other dyes derived from thiazine
• 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 the blood disorder was caused by nitrite during treatment for cyanide poisoning
• if the blood disorder was caused by chlorate poisoning.

Warnings and precautions

Consult your doctor or nurse before receiving Methylthioninium Chloride Proveblue

• If you have moderate or severe kidney disease; a lower single dose is required (maximum 1 to 2 mg/kg)
• if your blood disorder was caused by a chemical called aniline, found in dyes; the dose may need to be reduced, and the total cumulative dose must not exceed 4 mg/kg (see section 3 of this leaflet)
• if your blood disorder was caused by a medication called dapsone (used to treat leprosy and other skin diseases); the dose may need to be reduced, and the total cumulative dose must not exceed 4 mg/kg (see section 3)
• if you have hyperglycaemia or diabetes mellitus, as these conditions could worsen due to the glucose solution used to dilute the medicine
• your urine and faeces may turn greenish-blue and your skin may become bluish during treatment with Methylthioninium Chloride Proveblue. This colour change is expected and will disappear once treatment ends.

If any of the above situations apply to you, consult your doctor.

Photosensitivity

Methylthioninium chloride may cause a photosensitivity reaction in the skin (a reaction similar to sunburn) when exposed to intense light sources, such as phototherapy, operating room lights, and pulse oximeters.

Protective measures against light exposure 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 aged 3 months or younger, lower doses are recommended (see section 3 of this leaflet).

Other medicines and Methylthioninium Chloride Proveblue

Tell your doctor, pharmacist, or nurse if you are using, have recently used, or might need to use any other medicines.

You must not receive Methylthioninium Chloride if you are taking certain medicines used to treat depression or anxiety that affect a brain chemical called serotonin. When used together with these medicines, methylthioninium chloride may cause serotonin syndrome, which can be potentially fatal. These 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.

However, if intravenous administration of Methylthioninium Chloride cannot be avoided, you should receive the lowest possible dose and be monitored for 4 hours after administration.

If you have any doubts about whether you should receive this medicine, consult your doctor.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before receiving this medicine.

The use of Methylthioninium Chloride Proveblue during pregnancy is not recommended unless clearly necessary, for example, in a potentially life-threatening situation.

Due to lack of data on whether methylthioninium chloride passes into human milk, breastfeeding must be interrupted for 8 days after treatment with this medicine.

Driving and using machines

Do not drive or operate tools or machinery, as methylthioninium chloride has a moderate influence on the ability to drive and use machines.

3. How Cloruro de metiltionio Proveblue is administered

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

Adults, children over 3 months of age, and elderly patients

The usual dose is 1 to 2 mg per kilogram of body weight, i.e., 0.20 to 0.4 ml per kilogram, administered over a period of 5 minutes. A second dose may be given after one hour if necessary.

The maximum recommended cumulative dose throughout treatment is 7 mg/kg.

If the blood disorder has been caused by aniline or dapsone, the total cumulative dose must not exceed 4 mg/kg (see section 2).

Treatment is generally not expected to last longer than one day.

Patients with renal impairment

In infants over 3 months of age, children, adolescents, and adults, the recommended dose in patients with moderate renal impairment (eGFR 30–59 ml/min/1.73m²) is 1–2 mg/kg body weight. If a dose of 1 mg/kg is administered, 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 methemoglobin levels remain significantly above the normal clinical range. The maximum recommended cumulative dose for the treatment cycle is 2 mg/kg.

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

Methylene blue chloride should be used with caution in infants aged 3 months or younger and in newborns with moderate or severe renal impairment (eGFR 15–59 ml/min/1.73m²), as there are no available data and methylene blue chloride is predominantly eliminated via the kidneys. Lower cumulative maximum doses (<0.5 mg/kg body weight) may be considered.

Dose adjustment is not recommended in patients with mild renal impairment (eGFR 60–89 ml/min/1.73m²).

Infants aged 3 months or younger

The recommended dose is 0.3 to 0.5 mg/kg body weight, i.e., 0.06 to 0.1 ml/kg, administered 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 administered after one hour if symptoms persist or recur. Treatment generally should not last longer than one day.

This medicine may be diluted in 50 ml of 5% glucose solution for injection (50 mg/ml) to avoid local pain, especially in children.

If you receive more Cloruro de metiltionio Proveblue than you should

Since this medicine will be administered while you are in the hospital, it is unlikely that you will receive too much or too little. However, inform your doctor if you experience any of the following adverse reactions:

• nausea
• stomach pain
• chest pain
• dizziness
• headache
• sweating
• confusion
• increased methemoglobin (an abnormal form of hemoglobin in the blood)
• high blood pressure
• difficulty breathing
• abnormally fast heartbeat
• tremor
• skin color changes (skin may turn bluish)
• reduction in red blood cell count, which may cause paleness, shortness of breath, and weakness
• jaundice (yellowing of the skin and eyes); reported only in infants

If you have any further questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, Cloruro de metiltionio Proveblue may produce adverse effects, although not everyone experiences them.

These effects are identical in adults and children, except for jaundice, which has only been reported in infants.

• Very common adverse effects (may affect more than 1 in 10 people):

• limb pain

• dizziness

• sweating

• skin color changes. The skin may turn bluish

• blue or green urine

• numbness and tingling

• abnormal taste in the mouth

• nausea

• Common adverse effects (may affect up to 1 in 10 people):

• stomach pain

• chest pain

• headache

• anxiety

• injection site pain

• vomiting

• Frequency not known (frequency cannot be estimated from available data):

• serotonin syndrome when Cloruro de metiltionio Proveblue is taken with certain medicines used to treat depression or anxiety, see section 2

• reduction in hemoglobin levels (the protein in red blood cells that carries oxygen in the blood) in blood tests

• reduction in the number of red blood cells, which may cause paleness, shortness of breath, and weakness

• tissue damage at the injection site

• jaundice (yellowing of the skin and eyes); only reported in infants

• difficulty speaking

• increased or decreased blood pressure

• agitation

• lack of oxygen

• irregular heartbeats, including abnormally slow or fast heartbeat

• severe allergic reactions (called anaphylactic reaction, which may cause swelling of the throat or face, difficulty breathing, or severe rash)

• increased methemoglobin (an abnormal form of hemoglobin in the blood)

• breathing difficulty

• confusion

• tremor

• hives

• fever

• rapid breathing

• pupil dilation

• change in stool color. Stools may appear greenish or bluish

• increased skin sensitivity to light (photosensitivity).

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Methylthioninium Chloride Proveblue

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

Do not use this medicine after the expiry date stated on the carton and on the labels of the ampoule, following EXP. The expiry date refers to the last day of the month indicated. The doctor or nurse will check that the expiry date shown on the label has not passed before administering the injection.

Do not refrigerate or freeze. Store the ampoule in the original packaging to protect it from light.

The medicine should be used immediately after opening or dilution.

Do not use Methylthioninium Chloride Proveblue if the solution has changed colour, is cloudy, or contains precipitates or particles.

Any unused medicine and materials that have come into contact with it should be disposed of in accordance with local regulations.

6. Contents of the pack and other information

Composition of Methylthioninium Chloride Proveblue

• The active substance is methylthioninium chloride.

Each ml of solution contains 5 mg of methylthioninium chloride.

Each 10 ml ampoule contains 50 mg of methylthioninium chloride.

Each 2 ml ampoule contains 10 mg of methylthioninium chloride.

• The other component is water for injections.

Appearance of the product and contents of the pack

Methylthioninium Chloride Proveblue is a clear, dark blue injectable solution (injection) supplied in clear glass ampoules.

Each carton contains a tray with 5 ampoules of 10 ml.

Each carton contains a tray with 5 ampoules of 2 ml.

Each carton contains a tray with 20 ampoules of 2 ml.

Marketing Authorization Holder

Provepharm SAS
22 rue Marc Donadille, 13013 Marseille, France

Manufacturer

Pierrel S.p.A.
s.s. Appia 7 bis, 46/48, 81043 Capua, Italy

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

For further information on this medicinal product, please contact the local representative of the Marketing Authorization Holder:

Date of the most recent review of this leaflet:

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

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This information is intended for healthcare professionals only:

Preparation for intravenous administration

Use the product immediately after opening. Inject very slowly over 5 minutes.

Methylthioninium chloride Proveblue is hypotonic and may be diluted in 50 ml of 5% glucose injection solution (50 mg/ml) to avoid local pain, especially in the paediatric population. It must not be diluted in 9 mg/ml (0.9%) sodium chloride injection solution, as chloride has been shown to reduce the solubility of methylthioninium chloride.

Additional information on the administration of Methylthioninium chloride Proveblue is provided in section 3 of the leaflet.

Disposal of unused medicine and of all materials that have come into contact with it must be carried out in accordance with local regulations.