METHYLTHIONINIUM CHLORIDE PROVEBLUE 5 mg/ml INJECTABLE SOLUTION

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 further questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse, even if you think they might be unrelated to the medicine. See section 4.

Contents of the Package Leaflet

1. What is Methylthioninium Chloride Proveblue and what is it used for
2. What you need to know before you are given Methylthioninium Chloride Proveblue
3. How Methylthioninium Chloride Proveblue is administered
4. Possible side effects
5. Storage of Methylthioninium Chloride Proveblue
6. Contents of the pack and further information

1. What is Methylthioninium Chloride Proveblue and what is it used for

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

Methylthioninium Chloride Proveblue will be administered to you or your child (0-17 years) to treat blood problems caused by exposure to certain medicines or chemicals that can cause a disease called methaemoglobinaemia.

In methaemoglobinaemia, the blood contains too much methaemoglobin (an abnormal form of haemoglobin that cannot carry oxygen around the body effectively).

This medicine will help to normalise the haemoglobin and restore oxygen transport in the blood.

2. What you need to know before you are given Methylthioninium Chloride Proveblue

You must not be given Methylthioninium Chloride Proveblue:

• if you are allergic to methylthioninium chloride or to other thiazine derivatives
• 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 has been caused by nitrite during treatment of cyanide poisoning
• if the blood disorder was 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 kidney disease; the dose may need to be reduced (< 1 mg/kg)
• if your blood disorder has been 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 has been caused by a medicine 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 may worsen due to the glucose solution used for dilution of the medicine

• urine and stools may turn a blue-green colour and the skin may turn blue when you are treated with Methylthioninium Chloride Proveblue. This colour change is expected and will disappear when treatment is stopped.

If any of the above applies to you, talk to your doctor.

Photosensitivity

Methylthioninium chloride may cause a photosensitivity reaction on the skin (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 have monitoring tests during and after treatment with Methylthioninium Chloride Proveblue.

Children

Special care is needed with Methylthioninium Chloride Proveblue:

• in newborns and infants under 3 months, 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 or have recently used or might use any other medicines.

You must not be given Methylthioninium Chloride if you are taking certain medicines for depression or anxiety that affect a chemical in the brain called serotonin. If used together, methylthioninium chloride can cause serotonin syndrome, which can be life-threatening. These medicines are:

• selective serotonin reuptake inhibitors (SSRIs) such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and zimeldine
• bupropion
• buspirone
• clomipramine
• mirtazapine
• venlafaxine
• monoamine oxidase inhibitors.

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

If you are unsure whether you should be given this medicine, talk to 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 being given this medicine.

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

Due to the lack of data on whether methylthioninium chloride passes into human milk, breast-feeding should be interrupted for 8 days after treatment with this medicine.

Driving and Using Machines

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

3. How Methylthioninium Chloride Proveblue is Administered

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

Adults, Children Over 3 Months, and Elderly

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 administered after one hour if necessary.

The maximum recommended cumulative dose during the entire 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 should not usually last more than one day.

Infants Under 3 Months

The recommended dose is 0.3 to 0.5 mg/kg of body weight, i.e. 0.06 to 0.1 ml/kg, administered over a period of 5 minutes.

A repeated dose (0.3 to 0.5 mg/kg of body weight, i.e. 0.06-0.1 ml/kg) may be administered after one hour in case of persistence or recurrence of symptoms. Treatment should not usually last more than one day.

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

If You Receive More Methylthioninium Chloride Proveblue Than You Should

Since this medicine will be administered to you while you are in the hospital, it is unlikely that you will receive too much or too little; however, tell your doctor if you notice any of the following side effects:

• nausea
• stomach pain
• chest pain
• dizziness
• headache
• sweating
• confusion
• increased methaemoglobin (an abnormal form of haemoglobin in the blood)
• high blood pressure
• breathing difficulties
• abnormal heart rhythm
• tremor
• skin colour changes (your skin may turn blue)
• reduction in the number of red blood cells, which can cause paleness, shortness of breath, and weakness
• jaundice (yellowing of the skin and eyes); only reported in infants

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

4. Possible Side Effects

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 for jaundice, which has only been reported in infants.

• Very Common Side Effects(may affect more than 1 in 10 people)

• pain in the limbs
• dizziness

• sweating
• skin colour changes. Your skin may turn blue
• blue or green urine
  • numbness and tingling
  • abnormal taste in the mouth
  • nausea

• Common Side Effects(may affect up to 1 in 10 people):

• stomach pain
• chest pain
• headache
• anxiety
• pain at the injection site
• vomiting

• Frequency Not Known(frequency cannot be estimated from the available data):

• serotonin syndrome when Methylthioninium Chloride Proveblue is taken with certain medicines for depression or anxiety, see section 2
• reduction of haemoglobin levels (a protein in red blood cells that carries oxygen in the blood) in blood tests
• reduction in the number of red blood cells, which can cause paleness, shortness of breath, and weakness
• tissue damage at the injection site
• jaundice (yellowing of the skin and eyes); only reported in infants
• speech problems
• increased or decreased blood pressure
• agitation
• lack of oxygen
• irregular heartbeats, including abnormally slow or fast heart rate
• severe allergic reactions (anaphylactic reaction, which can cause swelling of the throat or face, difficulty breathing, or a severe rash)
• increased methaemoglobin (an abnormal form of haemoglobin in the blood)
• breathing difficulties
• confusion
• tremor
• hiccups
• fever
• rapid breathing
• dilated pupils
• change in stool colour. Stools may appear green or blue
• increased sensitivity of the skin to light (photosensitivity).

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist, or nurse, even if you think they might be unrelated to the medicine. 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.

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 which is stated on the carton and on the label of the ampoule after EXP. The expiry date refers to the last day of the month stated.

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 shows signs of change, is cloudy or contains precipitates or particles.

Disposal of unused medicine and all materials that have come into contact with it should be done according to local regulations.

6. Contents of the Pack and Further 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 ingredient is water for injections.

Appearance and Packaging

Methylthioninium Chloride Proveblue is a clear, dark blue solution for injection, supplied in transparent 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 Authorisation 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

You can obtain further information on this medicine from the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien

Lamepro B.V.

Tel: + 31 (0) 76-5600030

Lietuva

Provepharm SAS

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

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Provepharm SAS

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

Luxembourg/Luxemburg

Lamepro B.V.

Tel: + 31 (0) 76-5600030

Ceskárepublika

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

Lamepro 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

Ελλ?δα

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

AB 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

Ireland

Laboratoires ETHYPHARM

Tel: + 33 1 41 12 65 63

România

Dynamic Medical Solutions

Tel: + 40 (0)725596648

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

Medac Pharma S.r.l.

Tel: + 39 06 51 59 121

Suomi/Finland

Pharmanovia A/S

Puh/Tel: + 45 33 33 76 33

Κ?προς

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

United Kingdom

Martindale Pharmaceuticals Ltd

Tel: + 44 (0)1277 266600

Date of Last Revision

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 only for healthcare professionals:

Preparation for Intravenous Administration

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

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

Section 3 of the leaflet provides additional information on the administration of Methylthioninium Chloride Proveblue.

Disposal of unused medicine and all materials that have come into contact with it should be done according to local regulations.