METHYLTHIONINIUM CHLORIDE PHEBRA

Methylthioninium Chloride Phebra is for administration by a healthcare professional. Methylthioninium Chloride Phebra should be administered orally or by intravenous (IV) injection. In the treatment of acute methaemoglobinaemia, the IV route of administration is usually preferred because it provides a more rapid onset of effect.

However, in large doses, Methylthioninium Chloride can itself produce methaemoglobinaemia and the methaemoglobin concentration should therefore be closely monitored during treatment. e. 2 ml/kg body weight) injected over a period of at least five minutes.

A repeat dose may be given not less than 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 7 mg/kg and should not be exceeded.

4). The available data are insufficient to support a dose recommendation for continuous infusion. Oral Use When treatment is less urgent, and for chronic dosing of genetic methaemoglobinaemia, Methylthioninium Chloride Phebra 3-6 mg/kg (generally 300 mg daily in adults) is given orally in divided doses over 24 hours with ascorbic acid 500 mg daily.

A suitable dilution for oral dosing would be 5-10 ml of the 1% solution diluted to 100-200 ml with water for injection. The high volume is suggested to reduce the degree of gastrointestinal disturbance and dysuria. The dosage of Methylthioninium Chloride should be calculated on the basis of lean bodyweight.

Special populations Elderly No dose adjustment is necessary. Renal impairment Methylthioninium Chloride Phebra should be used with caution in patients with moderate renal disease since there is limited data available and Methylthioninium Chloride is predominantly eliminated renally.

Lower doses (<1 mg/kg) may be needed. 3). 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. e. 05 ml/kg body weight, given over a period of at least five minutes. e. 4 for important safety information).

Method of administration Intravenous use:

Methylthioninium Chloride Phebra may be diluted in 50 ml glucose 50 mg/ml (5%) solution for injection to avoid local pain, in particular in the paediatric population. It must be injected very slowly over a period of at least five minutes.

It must not be administered by subcutaneous or intrathecal injection. 6.

Oral Use:

A suitable dilution for oral dosing would be 5-10 ml of the 1% solution diluted to 100-200 ml with water for injection. The high volume is suggested to reduce the degree of gastrointestinal disturbance and dysuria.

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. Oral Administration Oral administration may cause gastrointestinal disturbances (nausea, vomiting and diarrhoea) and dysuria.

Intravenous Administration After intravenous administration, Methylthioninium Chloride may cause nausea, vomiting, abdominal and chest pain, headache, dizziness, mental confusion and profuse sweating. 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 Abdominal pain Common Vomiting Common Faeces discolouration (blue-green) Not known Skin and subcutaneous tissue disorders Skin discolouration (blue) Very common Sweating Very common Urticaria Not known Phototoxicity / Photosensitivity Not known Renal and urinary disorders Cromaturia (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 1Reported in infants only Use of Methylthioninium Chloride for endoscopic tattoo (not an approved indication) has been associated with vascular necrosis, mucosal ulceration, mural necrosis, extramural fat necrosis and inflammatory changes in the colon.

Injection of Methylthioninium Chloride into joint space (not an approved indication) has resulted in effusion in the treated joint. Paediatric population Adverse reactions are the same as in adults (except hyperbilirubinaemia, reported in infants only).

High Doses With very high doses methaemoglobinaemia and haemolysis may occur. Infants and patients with glucose-6-phosphate dehydrogenase deficiency are particularly susceptible to haemolysis from treatment with Methylthioninium Chloride.

High doses, if not adequately diluted, could cause thrombophlebitis. Not more than 350 mg of Methylthioninium Chloride should be diluted in each 500 ml of infusion fluid. Blue Colouration Methylthioninium Chloride imparts a blue colour to the skin, saliva, oral mucosa and teeth, and a blue-green colour to urine and faeces.

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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Long term administration of Methylthioninium Chloride may result in marked anaemia due to accelerated destruction of erythrocytes; haemoglobin concentrations should be checked frequently. If Methylthioninium Chloride is injected subcutaneously or if extravasation occurs, necrotic abscesses may result.

Methylthioninium Chloride must be injected very slowly over a period of at least five minutes to prevent high local concentrations of the compound from producing additional methaemoglobin. It imparts a blue-green colour to urine and 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 can exacerbate dapsone-induced haemolytic anaemia 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.

Anaesthetists should be vigilant for methaemoglobinaemia in patients receiving dapsone therapy and for BIS (Bispectral Index) interference with Methylthioninium Chloride 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. 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.

• Use in pregnancy and lactation is contraindicated as its safe use during pregnancy has not yet been established. • Patients with severe renal impairment • Hypersensitivity to the active substance, or to any other thiazine dyes • Patients with methaemoglobinaemia due to chlorate poisoning as Methylthioninium Chloride may convert the chlorate to hypochlorite which is an even more toxic compound.

• Patients with methaemoglobinaemia as a direct consequence of treating cyanide poisoning with sodium nitrite • Patients with glucose-6-phosphate dehydrogenase deficiency, due to the risk of haemolytic anaemia • Deficiency in NAPDH reductase • Intrathecal injection of Methylthioninium Chloride which can result in neural damage