Methylthioninium chloride Proveblue

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

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1. NAME OF THE MEDICINAL PRODUCT 

 

Methylthioninium chloride Proveblue 5 mg/ml solution for injection 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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. 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Solution for injection (injection)  

Clear dark blue solution with a pH value between 3.0 and 4.5 

Osmolality is usually between 10 and 15 mOsm/kg.  

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Acute symptomatic treatment of medicinal and chemical products-induced methaemoglobinaemia.  

Methylthioninium chloride Proveblue is indicated in adults, children and adolescents (aged 0 to 

17 years old). 

 

4.2 Posology and method of administration 
 

Methylthioninium chloride Proveblue is for administration by a healthcare professional.   

 

Posology 

 

Adults  

 

The usual dose is 1 to 2 mg per kg body weight, i.e. 0.2-0.4 ml per kg body weight, given over a 

period of 5 minutes.  

A repeat dose (1 to 2 mg/kg body weight, i.e. 0.2-0.4 ml/kg body weight) 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. 

Treatment does not usually exceed one day. 

The maximum recommended cumulative dose for the course of treatment is 7 mg/kg and should not be 

exceeded, since Methylthioninium chloride administered above the maximum dose may cause 

methaemoglobinaemia in susceptible patients.  

In the case of aniline- or dapsone-induced methaemaglobinaemia, the maximum recommended 

cumulative dose for the course of treatment is 4 mg/kg (see section 4.4).  

Too limited data are available to support a continuous infusion dose recommendation. 

 

 



 

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Special populations 

 

Elderly 

 

No dose adjustment is necessary. 

 

Renal impairment 

 

Methylthioninium chloride should be used with caution in patients with moderate to severe renal 

disease since there is limited data available and methylthioninium chloride is predominantly renally 

eliminated. Lower doses (<1 mg/kg) may be needed.  

 

Hepatic impairment 

 

There is no experience in patients with severe hepatic impairment.  

 

Paediatric population 

 

Infants above 3 months, children and adolescents:  

Same posology as for adults.  

Infants 3 months old or younger and newborn infants:  

The recommended dose is 0.3-0.5 mg/kg body weight, i.e. 0.06 to 0.1 ml/kg body weight, given 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 body weight) 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 (see section 4.4 for important safety information). 

Treatment does not usually exceed one day. 

 

Method of administration  

 

For intravenous use. 

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 be injected very slowly over a period of 5 minutes. 

It must not be administered by subcutaneous or intrathecal injection. 

For instructions on handling and dilution of the medicinal product before administration, see section 

6.6. 

 

4.3 Contraindications 

 

• Hypersensitivity to the active substance, or to any other thiazine dyes 

• Patients with Glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of 
haemolytic anaemia 

• Patients with nitrite-induced methaemoglobinaemia during treatment of cyanide poisoning 

• Patients with methaemoglobinaemia due to chlorate poisoning 

• Deficiency in NADPH (nicotinamide adenine dinucleotide phosphate) reductase. 
 

4.4 Special warnings and precautions for use 

 

General 

 

Methylthioninium chloride Proveblue must be injected very slowly over a period of 5 minutes to 

prevent high local concentrations of the compound from producing additional methaemoglobin.  



 

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It imparts a blue-green colour to urine, faeces and a blue colour to skin which may hinder a diagnosis 

of cyanosis. 

In patients with aniline-induced methaemoglobinaemia, repeated doses of methylthioninium chloride 

may be required. Caution should be exercised in the course of treatment with methylthioninium 

chloride as this may exacerbate Heinz body formation and haemolytic anaemia. Lower doses should 

therefore be considered and total cumulative dose should not exceed 4 mg/kg. 

Methylthioninium chloride Proveblue can exacerbate dapsone-induced haemolytic anemia because 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. 

In cases of suspected methaemoglobinaemia, it is advisable to check the oxygen saturation by co-

oximetry when available since pulse oximetry may provide a false estimation of oxygen saturation 

during administration of methylthioninium chloride. 

Anaesthesiologists should be vigilant for methaemoglobinaemia in patients receiving dapsone therapy 

and for BIS (Bispectral Index) interference with Methylthioninium chloride Proveblue administration.  

Electrocardiogram (ECG) and blood pressure should be monitored during and after treatment with 

Methylthioninium chloride Proveblue as hypotension and cardiac arrhythmia are potential adverse 

reactions (see section 4.8). 

Failure to respond to methylthioninium chloride suggests cytochrome b5 reductase deficiency, 

glucose-6- phosphate dehydrogenase deficiency or sulfhaemoglobinemia. Alternative treatment 

options should be considered. 

Methylthioninium chloride may cause serious or fatal serotonergic syndrome when used in 

combination with serotonergic drugs. Avoid concomitant use of methylthioninium chloride with 

selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors 

(SNRIs), and monoamine oxidase inhibitors (see section 4.5). 

Patients treated with methylthioninium chloride in combination with serotonergic drugs should be 

monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, 

discontinue use of methylthioninium chloride, and initiate supportive treatment. 

 

Patients with hyperglycaemia or diabetes mellitus  

 

If diluted in glucose 50 mg/ml (5%) solution for injection, methylthioninium chloride must be used 

with caution in patients with hyperglycaemia or diabetes mellitus, as these conditions may be 

exacerbated by the glucose solution. 

 

Paediatric population 

 

Extreme caution should be exercised when administering to 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 methylthioninium chloride. 

 

Photosensitivity 

Methylthioninium chloride 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 



 

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occur after administration of methylthioninium chloride. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Methylthioninium chloride should be avoided in patients receiving medicinal products that enhance 

serotonergic transmission because of the potential for serious CNS reactions, including potentially 

fatal serotonin syndrome. These include SSRIs (selective serotonin reuptake inhibitors), bupropion, 

buspirone, clomipramine, mirtazapine, and venlafaxine. If the intravenous use of methylthioninium 

chloride cannot be avoided in patients treated with serotonergic medicinal products, the lowest 

possible dose should be chosen and the patient observed closely for central nervous system (CNS) 

effects for up to 4 hours after administration (see sections 4.4 and 4.8). 

Methylthioninium chloride is an in vitro inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. 

The clinical consequences of increases plasma concentration of co-administered drugs which are 

sensitive CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A substrates cannot be ruled out. 

Methylthioninium chloride is an in vitro inducer of CYP1A2. The clinical consequence is not known. 

The administration of methylthioninium chloride Proveblue has the potential to transiently increase or 

decrease the clearance of drugs that are primarily metabolized by these enzymes. The clinical 

consequences are however considered minimal since methylthioninium chloride Proveblue is used 

often only once and in an acute emergency setting. 

Methylthioninium chloride is a potent inhibitor of the transporters OCT2, MATE1 and MATE2-K. 

The clinical consequences of the inhibition are not known. The administration of methylthioninium 

chloride Proveblue 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.  

Methylthioninium chloride 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. 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

 

There are no adequate data from the use of methylthioninium chloride in pregnant women. Studies in 

animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. 

Methylthioninium chloride Proveblue should not be used during pregnancy unless clearly necessary, 

e.g. in life-threatening methaemoglobinaemia.  

 

Breast-feeding 

 

It is unknown whether methylthioninium chloride is excreted in human breast milk. The excretion of 

methylthioninium chloride in milk has not been studied in animals. A risk to the suckling child cannot 

be excluded. Based on kinetic data, breast-feeding should be discontinued for up to 8 days after 

treatment with Methylthioninium chloride Proveblue. 

 

Fertility 

 

In vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dose 

dependant manner. 
 

4.7 Effects on ability to drive and use machines 

 

Methylthioninium chloride has moderate influence on the ability to drive and use machines. Indeed, 

driving can be affected due to confusional state, dizziness and possibly eye disturbances. 



 

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However, the risk is limited as the medicinal product is intended for acute administration only in 

emergency situations at hospital. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

The most commonly reported adverse reactions observed during clinical trials are dizziness, 

paraesthesia, dysgeusia, nausea, skin discoloration, chromaturia, sweating, injection site pain and pain 

in extremity. 

Intravenous injection of methylthioninium chloride has occasionally caused hypotension and cardiac 

arrhythmias, and such disorders might prove fatal on rare occasions. 

 

Tabulated list of adverse reactions 

 

The adverse reactions listed in the table below occur in adults, children and adolescents (aged 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.  

 

System organ class Adverse reactions Frequency 

Blood and lymphatic system 

disorders 

Methaemoglobinaemia,  Not known 

Hyperbilirubinaemia1 Not known  

Haemolytic anaemia Not known 

Immune system disorders Anaphylactic reactions Not known 

Psychiatric disorders Confusional state Not known 

Agitation Not known 

Nervous system disorders Dizziness Very common 

Headache Common 

Anxiety Common 

Tremor Not known 

Fever Not known 

Aphasia Not known 

Paraesthesia Very common 

Dysgeusia Very common 

Serotonin Syndrome with concomitant 

use of serotonergic drugs (see section 

4.4 and section 4.5). 

Not known 

Eye disorders Mydriasis Not known 

Cardiac disorders Cardiac arrhythmia Not known 

Tachycardia Not known 

Vascular disorders Hypertension Not known 

Hypotension Not known 

Respiratory, thoracic and 

mediastinal disorders 

Dyspnoea Not known 

Tachypnoea Not known 



 

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Hypoxia Not known 

Gastrointestinal disorders Nausea Very common 

Vomiting Common 

Abdominal pain Common 

Faeces discoloration (blue-green) Not known 

Skin and subcutaneous tissue 

disorders 

Skin discoloration (blue) Very common 

Sweating Very common 

Urticaria Not known 

Phototoxicity / Photosensitivity Not known 

Renal and urinary disorders Chromaturia (blue-green) Very common 

General disorders and 

administration site conditions 

Chest pain Common 

Local tissue necrosis at the injection 

site 

Not known 

Injection site pain Common 

Investigations Haemoglobin decreased Not known 

Musculoskeletal and connective 

tissue disorder 

Pain in extremity Very common 

1 Reported in infants only 

 

Paediatric population 

 

Adverse reactions are the same as in adults (except hyperbilirubinaemia, reported in infants only). 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation 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 via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

Individuals without methaemoglobinaemia 

 

The administration of large intravenous doses (≥ 7 mg/kg) of Methylthioninium chloride Proveblue 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. 

Individuals with methaemoglobinaemia 

 

Cumulative doses of Methylthioninium chloride may lead to dyspnoea and tachypnoea, presumably 

related to reduced oxygen availability caused by methaemoglobinaemia, chest pain, tremor, cyanosis 

and haemolytic anaemia. 



 

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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. 

 

Paediatric population 

 

Hyperbilirubinaemia has been observed in infants after administration of 20 mg/kg methylthioninium 

chloride. 

Death occurred in 2 infants after administration of 20 mg/kg methylthioninium chloride. Both infants 

had complex medical circumstances and methylthioninium chloride was only partially responsible.  

The patient should be maintained under observation, the methaemoglobin level should be monitored 

and appropriate supportive measures taken as necessary.  

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: All other therapeutic products, antidotes, ATC code: V03AB17 

In vivo, in low concentration, methylthioninium chloride speeds up the conversion of methaemoglobin 

to haemoglobin. 

Methylthioninium chloride Proveblue has been observed to stain tissues selectively. Its use in 

parathyroid surgery (not indicated) has induced adverse CNS effects when administered concomitantly 

with serotonergic medicinal products (see section 4.5). 

 

Paediatric population 

 

The efficacy of methylthioninium chloride for the treatment of methaemoglobinaemia in peadiatric 

population was demonstrated in two retrospective studies and one open randomised clinical trial. Case 

reports of efficacy are also available in literature. 

Please refer to section 4.4 for important safety information.  

 

5.2 Pharmacokinetic properties 

 

After intravenous administration Methylthioninium chloride Proveblue is rapidly taken up by the 

tissues. It is also well absorbed by the oral route. The majority of the dose is excreted in the urine, 

usually in the form of leucomethylthioninium chloride. 

The estimated terminal half-life of methylthioninium chloride after intravenous administration is  

26.7h.  

Methylthioninium chloride Proveblue is not an in vitro inducer of CYP2B6 and CYP3A4. 

Methylthioninium chloride Proveblue is an in vitro inhibitor of P-gp. 

Methylthioninium chloride Proveblue is not an in vitro substrate for BCRP or OCT2 and is not an in 

vitro inhibitor of BCRP, OAT1 or OAT3. 

 

5.3 Preclinical safety data 

 

Repeated dose toxicity 

 



 

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One-month repeated dose toxicity in dogs showed no macroscopic toxic effects.  

Adverse reactions, seen at exposure levels similar to clinical exposure levels and with possible 

relevance to clinical use were moderate regenerative anaemia associated with increased mean platelet 

count and fibrinogen levels, a minimal increase in mean total bilirubin blood values and an increased 

incidence of moderate urine bilirubin levels. 

 

Genotoxicity 

 

Methylthioninium chloride was mutagenic in gene mutation assays in bacteria and mouse lymphoma 

cells but not in vivo mouse micronucleus assay when administered intravenously at 62 mg/kg.  

 

Carcinogenicity 

 

Some evidence of carcinogenic activity of methylthioniniul chloride has been shown in male mice and 

male rats. An equivocal evidence of carcinogenic activity was observed in female mice. No evidence 

of carcinogenic activity was observed in female rats. 

 

Reproductive Toxicology 

 

In vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dose 

dependant manner. 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 rats and rabbits, teratogenic effects have been reported, with foetal and maternal toxicity. In rats, 

increased resorption rates have been observed. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Water for injections 

 

6.2 Incompatibilities 

 

This medicinal product must not be mixed with other medicinal products except those mentioned in 

section 6.6. It must especially not be mixed with sodium chloride 9 mg/ml (0.9%) solution for 

injection because it has been demonstrated that chloride reduces the solubility of methylthioninium 

chloride. 

 

6.3 Shelf life 

 

3 years 

After opening or dilution: From a microbiological point of view, unless the method of 

opening/dilution precludes the risk of microbial contamination, the product must be used immediately. 

If not used immediately, in-use storage times and conditions are the responsibility of the user. 

 

6.4 Special precautions for storage 

 

Do not refrigerate or freeze. 

Keep the ampoule in the original package in order to protect from light. 

For storage conditions of the diluted medicinal product, see section 6.3. 

 

6.5 Nature and contents of container  
 

Type I glass ampoules.  

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

Each carton contains a tray with 5 or 20 ampoules of 2 ml in blister. 



 

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Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 

 

For single use only 

Methylthioninium chloride Proveblue may be diluted in 50 ml glucose 50 mg/ml (5%) solution for 

injection to avoid local pain, in particular in paediatric population. 

Before any administration, it is recommended to inspect the parenteral solutions to verify that they are 

free of particles. 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. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

PROVEPHARM SAS 

22 rue Marc Donadille, 13013 Marseille, France 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/11/682/001 

EU/1/11/682/002 

EU/1/11/682/003 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 06 May 2011 

Date of latest renewal: 08 February 2016 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 



 

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ANNEX II 

 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 

 



 

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A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers responsible for batch release 

 

Pierrel S.p.A. 

s.s. Appia 7 bis, 46/48 

IT-81043 Capua (CE) 

Italy 

Cenexi 

52, Rue Marcel et Jacques Gaucher  

94120 Fontenay-sous-Bois 

France 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

 C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

• Periodic Safety Update Reports 
 

The requirements for submission of periodic safety update reports for this medicinal product are 

set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 

Directive 2001/83/EC and any subsequent updates published on the European medicines web-

portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   

 

• Risk Management Plan (RMP) 

 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in 

the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 

subsequent updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



 

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ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 



 

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A. LABELLING 



 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Methylthioninium chloride Proveblue 5 mg/ml solution for injection 

methylthioninium chloride 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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 

 

 

3. LIST OF EXCIPIENTS 

 

Water for injections 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

5 ampoules of 10 ml 

 

50 mg/10 ml 

 

5 ampoules of 2 ml 

20 ampoules of 2 ml 

10 mg/2 ml 

 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Intravenous use only 

For slow intravenous injection  

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 



 

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8. EXPIRY DATE 

 

EXP  

The medicine must be used immediately after opening or dilution. 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not refrigerate or freeze. 

Keep the ampoule in the original package in order to protect from light. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

For single use only 

Any solution remaining in the opened ampoules must be discarded. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Provepharm SAS  

22 rue Marc Donadille, 13013 Marseille, France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/11/682/001 

EU/1/11/682/002 

EU/1/11/682/003 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 



 

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18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN: 

 



 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

AMPOULE 

 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Methylthioninium chloride Proveblue 5 mg/ml injection 

methylthioninium chloride 

Intravenous use only 

 

 

2. METHOD OF ADMINISTRATION 

 

 

 

3. EXPIRY DATE 

 

EXP  

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

50 mg/10 ml 

10 mg/2 ml 

 

 

6. OTHER 

 



 

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B. PACKAGE LEAFLET 



 

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Package leaflet: Information for the user 

 

Methylthioninium chloride Proveblue 5 mg/ml solution for injection 

Methylthioninium 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 further questions, ask your doctor or nurse. 
- If  you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4.  

 

What is in this leaflet 

 

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

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

3. How Methylthioninium chloride Proveblue is given   

4. Possible side effects 

5. How to store Methylthioninium chloride Proveblue   
6. Contents of the pack and other information 

 

 

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

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. 

 

 

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 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 doses (< 1 mg/kg) may be 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) 



 

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- 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 

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 



 

22 

Do not drive or use any tools or machines as methylthioninium chloride has moderate influence on the 

ability to drive and use machines.  

 

 

3. How Methylthioninium chloride Proveblue is given     
 

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. 

 

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. 

 

 



 

23 

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 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 



 

24 

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

safety of this medicine. 

 

 

5. How to store Methylthioninium chloride Proveblue   

 

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. 

 

 

6. Contents of the pack and other information 

 

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 

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 any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

  
 

België/Belgique/Belgien  

Lamepro B.V. 

Tél/Tel: + 31 (0) 76-5600030 

Lietuva 

Provepharm SAS 

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

 

 

 

 

 



 

25 

България 

Provepharm SAS 

Teл.: + 33 (0)4 91 08 69 30 

 

Luxembourg/Luxemburg 

Lamepro 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 

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 

 

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 

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 

 

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 

 

United Kingdom 

Martindale Pharmaceuticals Ltd 

Tel: + 44 (0)1277 266600 

 

 



 

26 

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/. 

 

 

<-------------------------------------------------------------------------------------------------------------------------- 

 

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. 

 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET