Methylthioninium Chloride Proveblue

Methylthioninium chloride Proveblue is for administration by a healthcare professional. e. 4 ml per kg body weight, given over a period of 5 minutes. e. 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.

4). Too limited data are available to support a continuous infusion dose recommendation. 3 Special populations Elderly No dose adjustment is necessary. 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.

2). 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. 73 m2) since there is no data available and methylthioninium chloride is predominantly renally eliminated.

5 mg/kg body weight) may be considered. 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 No recommendation regarding dose adjustment can be given based on available study data.

2.

Paediatric population Infants above 3 months, children and adolescents:

Same posology as for adults. e. 1 ml/kg body weight, given over a period of 5 minutes. e. 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. 6.

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. 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 national reporting system listed in Appendix V.

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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. 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. 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. 5 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.

• 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.