CLORURA DE METILTIONINIU PROVEBLUE 5mg / ml injectible solution medication leaflet

Methylthioninium chloride Proveblue 5 mg/ml solution for injection

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.

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.

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

Methylthioninium chloride Proveblue is indicated in adults, children and adolescents (aged 0 to17 years old).

Methylthioninium chloride Proveblue is for administration by a healthcare professional.

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 aperiod 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 afterthe first dose in cases of persistent or recurrent symptoms or if methaemoglobin levels remainsignificantly 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 beexceeded, since Methylthioninium chloride administered above the maximum dose may causemethaemoglobinaemia in susceptible patients.

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

No dose adjustment is necessary.

In infants above 3 months, children and adolescents and in adults, the recommended dosage in patientwith moderate renal impairment (eGFR 30-59 ml/min/1.73 m2) is 1-2 mg/kg per body weight. If a 1mg/kg dose is given, a repeat dose of 1 mg/kg may be given one hour after the first dose in cases ofpersistent or recurrent symptoms or if methaemoglobin levels remain significantly higher than thenormal clinical range. The maximum recommended cumulative dose for the course of treatment is2 mg/kg (see section 5.2).

In infants above 3 months, children and adolescents and in adults, the recommended dosage in patientwith severe renal impairment (eGFR 15-29 ml/min/1.73 m2) is a single dose of 1 mg/kg per bodyweight. 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 andnewborn infants with moderate to severe renal impairment (eGFR 15-59 ml/min/1.73 m2) since thereis no data available and methylthioninium chloride is predominantly renally eliminated. Lowermaximum 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/1.73m2).

The safety and efficacy of methylthioninium chloride in patients with end stage renal disease with andwithout dialysis has not yet been established. No data are available.

The safety and efficacy of methylthioninium chloride in patients with hepatic impairment has not yetbeen established.

No data are available.

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 aperiod 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 hourafter the first dose in cases of persistent or recurrent symptoms or if methaemoglobin levels remainsignificantly higher than the normal clinical range (see section 4.4 for important safety information).

Treatment does not usually exceed one day.

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 section6.6.

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

* Patients with Glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk ofhaemolytic 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.

Methylthioninium chloride Proveblue must be injected very slowly over a period of 5 minutes toprevent high local concentrations of the compound from producing additional methaemoglobin.

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

In patients with aniline-induced methaemoglobinaemia, repeated doses of methylthioninium chloridemay be required. Caution should be exercised in the course of treatment with methylthioniniumchloride as this may exacerbate Heinz body formation and haemolytic anaemia. Lower doses shouldtherefore be considered and total cumulative dose should not exceed 4 mg/kg.

Methylthioninium chloride Proveblue can exacerbate dapsone-induced haemolytic anemia because ofthe formation of the dapsone reactive metabolite hydroxylamine which oxidises haemoglobin. It isrecommended not to exceed a cumulative dose for the course of treatment of 4 mg/kg in patients withdapsone-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 saturationduring administration of methylthioninium chloride.

Anaesthesiologists should be vigilant for methaemoglobinaemia in patients receiving dapsone therapyand 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 adversereactions (see section 4.8).

Failure to respond to methylthioninium chloride suggests cytochrome b5 reductase deficiency,glucose-6- phosphate dehydrogenase deficiency or sulfhaemoglobinemia. Alternative treatmentoptions should be considered.

Methylthioninium chloride may cause serious or fatal serotonergic syndrome when used incombination with serotonergic drugs. Avoid concomitant use of methylthioninium chloride withselective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors(SNRIs), monoamine oxidase inhibitors and opioids (see section 4.5).

Patients treated with methylthioninium chloride in combination with serotonergic drugs should bemonitored 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 usedwith caution in patients with hyperglycaemia or diabetes mellitus, as these conditions may beexacerbated by the glucose solution.

Extreme caution should be exercised when administering to newborns and infants below the age of3 months due to lower concentrations of NADPH-methaemoglobin reductase necessary for reducingmethaemoglobin to haemoglobin, making these infants more susceptible to methaemoglobinaemiaproduced by high doses of methylthioninium chloride.

Methylthioninium chloride may cause a cutaneous photosensitivity reaction when exposed to stronglight sources, such as phototherapy, those found in operating theatres or locally from illuminatingdevices such as pulse oximeters.

Advise patients to take protective measures against exposure to light, because photosensitivity mayoccur after administration of methylthioninium chloride.

Methylthioninium chloride should be avoided in patients receiving medicinal products that enhanceserotonergic transmission because of the potential for serious CNS reactions, including potentiallyfatal serotonin syndrome. These include SSRIs (selective serotonin reuptake inhibitors), bupropion,buspirone, clomipramine, mirtazapine, and venlafaxine. Opioids, for example, tramadol, fentanyl,pethidine, and dextromethorphan, may also increase the risk of developing serotonin syndrome, whenused in combination with methylthioninium chloride. If the intravenous use of methylthioniniumchloride cannot be avoided in patients treated with serotonergic medicinal products, the lowestpossible 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 a potent reversible inhibitor of monoamine oxidase (see section 4.4).

Methylthioninium chloride is an in vitro inducer of CYP1A2. This interaction is not consideredclinically relevant, since treatment with Methylthioninium chloride does not usually exceed one day.

In a drug interaction study, a single IV dose of 2 mg/kg Methylthioninium chloride Proveblue did nothave a clinically relevant effect on the pharmacokinetics of midazolam (CYP3A4), caffeine(CYP1A2), omeprazole (CYP2C19), warfarin (CYP2C9), and dextromethorphan (CYP2D6).

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 methylthioniniumchloride Proveblue has the potential to transiently increase the exposure of drugs primarily cleared byrenal transport involving the OCT2/MATE pathway, including cimetidine, metformin and acyclovir.

Methylthioninium chloride is a substrate of P-glycoprotein (P-gp). The clinical consequences areconsidered likely to be minimal due to the transient and single dose use that normally occurs in theemergency setting.

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

It is unknown whether methylthioninium chloride is excreted in human breast milk. The excretion ofmethylthioninium chloride in milk has not been studied in animals. A risk to the suckling child cannotbe excluded. Based on kinetic data, breast-feeding should be discontinued for up to 8 days aftertreatment with Methylthioninium chloride Proveblue.

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

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.

However, the risk is limited as the medicinal product is intended for acute administration only inemergency situations at hospital.

The most commonly reported adverse reactions observed during clinical trials are dizziness,paraesthesia, dysgeusia, nausea, skin discoloration, chromaturia, sweating, injection site pain and painin extremity.

Intravenous injection of methylthioninium chloride has occasionally caused hypotension and cardiacarrhythmias, and such disorders might prove fatal on rare occasions.

The adverse reactions listed in the table below occur in adults, children and adolescents (aged 0 to17 years old) after intravenous administration. The frequencies are not known (cannot be estimatedfrom 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 Methaemoglobinaemia, Not knowndisorders

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 Not knownuse of serotonergic drugs (see section4.4 and section 4.5).

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 Dyspnoea Not knownmediastinal disorders

Tachypnoea Not known

Hypoxia Not known

Gastrointestinal disorders Nausea Very common

Vomiting Common

Abdominal pain Common

Faeces discoloration (blue-green) Not known

Skin and subcutaneous tissue Skin discoloration (blue) Very commondisorders

Sweating Very common

Urticaria Not known

Phototoxicity/Photosensitivity Not known

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

General disorders and Chest pain Commonadministration site conditions

Local tissue necrosis at the injection Not knownsite

Injection site pain Common

Investigations Haemoglobin decreased Not known

Musculoskeletal and connective Pain in extremity Very commontissue disorder1 Reported in infants only

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Individuals without methaemoglobinaemia

The administration of large intravenous doses (≥ 7 mg/kg) of Methylthioninium chloride Proveblue toindividuals without methaemoglobinaemia induces nausea and vomiting, chest tightness, chest pain,tachycardia, apprehension, severe sweating, tremor, mydriasis, blue-green staining of the urine, bluestaining 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, presumablyrelated to reduced oxygen availability caused by methaemoglobinaemia, chest pain, tremor, cyanosisand haemolytic anaemia.

Haemolytic anaemia has also been reported in case of severe overdose (20-30 mg/kg) in infants andadults with methaemoglobinaemia caused by aniline or chlorates. Haemodialysis may be used inpatients with severe haemolysis.

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

Death occurred in 2 infants after administration of 20 mg/kg methylthioninium chloride. Both infantshad complex medical circumstances and methylthioninium chloride was only partially responsible.

The patient should be maintained under observation, the methaemoglobin level should be monitoredand appropriate supportive measures taken as necessary.

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

In vivo, in low concentration, methylthioninium chloride speeds up the conversion of methaemoglobinto haemoglobin.

Methylthioninium chloride Proveblue has been observed to stain tissues selectively. Its use inparathyroid surgery (not indicated) has induced adverse CNS effects when administered concomitantlywith serotonergic medicinal products (see section 4.5).

The efficacy of methylthioninium chloride for the treatment of methaemoglobinaemia in peadiatricpopulation was demonstrated in two retrospective studies and one open randomised clinical trial. Casereports of efficacy are also available in literature.

Please refer to section 4.4 for important safety information.

After intravenous administration Methylthioninium chloride Proveblue is rapidly taken up by thetissues. 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 mean (SD) terminal half-life of methylthioninium chloride after intravenous administration is 24.7(7.2) h.

After a single 1 mg/kg dose of methylthioninium chloride, AUC0-96h increased by 52%, 116%, and192% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 - 89 ml/min/1.73 m2),moderate (eGFR 30-59 ml/min/1.73m2), and severe (eGFR 15-29 ml/min/1.73m2) renal impairment,respectively. Cmax increased by 42%, 34%, and 15% in subjects with mild, moderate, and severerenal impairment respectively. The half-life was unchanged in patients with mild to moderate renalimpairment. A longer mean half-life of 33 h were reported in subjects with severe renal impairment.

The AUC0-96h of Azure B after a single 1 mg/kg dose increased by 29%, 94%, and 339% in subjectswith mild (estimated glomerular filtration rate (eGFR) 60 - 89 ml/min/1.73 m2), moderate (eGFR 30-59 ml/min/1.73m2), and severe (eGFR 15-29 ml/min/1.73m2) renal impairment, respectively. Cmaxincreased by 23%, 13%, and 65% in subjects with mild, moderate, and severe renal impairmentrespectively.

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 invitro inhibitor of BCRP, OAT1 or OAT3.

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 possiblerelevance to clinical use were moderate regenerative anaemia associated with increased mean plateletcount and fibrinogen levels, a minimal increase in mean total bilirubin blood values and an increasedincidence of moderate urine bilirubin levels.

Methylthioninium chloride was mutagenic in gene mutation assays in bacteria and mouse lymphomacells but not in vivo mouse micronucleus assay when administered intravenously at 62 mg/kg.

Some evidence of carcinogenic activity of methylthioninium chloride has been shown in male mice andmale rats. An equivocal evidence of carcinogenic activity was observed in female mice. No evidence ofcarcinogenic activity was observed in female rats.

Reproductive Toxicology

In vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dosedependant manner. It has also been shown to inhibit the growth of cultured two-cell mouse embryos andthe 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.

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6. It must especially not be mixed with sodium chloride 9 mg/ml (0.9%) solution forinjection because it has been demonstrated that chloride reduces the solubility of methylthioniniumchloride.

4 years

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

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.

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.

Not all pack sizes may be marketed.

For single use only

Methylthioninium chloride Proveblue may be diluted in 50 ml glucose 50 mg/ml (5%) solution forinjection to avoid local pain, in particular in paediatric population.

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

PROVEPHARM SAS22 rue Marc Donadille, 13013 Marseille, France

EU/1/11/682/001

EU/1/11/682/002

EU/1/11/682/003

Date of first authorisation: 06 May 2011

Date of latest renewal: 08 February 2016

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

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