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.

Special populations

Elderly

No dose adjustment is necessary.

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 (see section 5.2).

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).

The safety and efficacy of methylthioninium chloride in patients with end stage renal disease with and without dialysis has not yet been established. No data are available.

Hepatic impairment

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

No data are available.

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.

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), monoamine oxidase inhibitors and opioids (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 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. Opioids, for example, tramadol, fentanyl, pethidine, and dextromethorphan, may also increase the risk of developing serotonin syndrome, when used in combination with methylthioninium chloride. 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 a potent reversible inhibitor of monoamine oxidase (see section 4.4).

Methylthioninium chloride is an in vitro inducer of CYP1A2. This interaction is not considered clinically 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 not have 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 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.

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

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 Yellow Card Sheme at: www.mhra.gov.uk/yellowcard

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.

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.