Drugs List

Therapeutic Indications

Uses

Treatment of drug-induced methaemoglobinaemia

Medicinal and chemical products-induced methaemoglobinaemia.

Administration

For intravenous injection only. The solution should be injected slowly, over a period of 5 minutes in order to prevent high local concentrations of the compound from producing additional methaemoglobin.

The concentrate for solution for injection may be diluted to avoid local pain especially in children. Consult product information.

Contraindications

G6PD deficiency
NADPH-dependent methaemoglobin reductase deficiency
Severe renal impairment

Precautions and Warnings

Children under 3 months
Methaemoglobinaemia due to chlorate poisoning
Nitrite-induced methaemoglobinaemia during treatment of cyanide poisoning
Breastfeeding
Diabetes mellitus
Hyperglycaemia
Moderate renal impairment
Pregnancy
Severe hepatic impairment

Advise ability to drive/operate machinery may be affected by side effects
Administer IV injection slowly
Large dose may cause methaemoglobinaemia - monitor levels closely
Monitor blood pressure and ECG continuously throughout treatment
Monitor haemoglobin levels
Monitor patients for signs and symptoms of Serotonin Syndrome
Advise patient to expect blue-green discolouration of the urine
Discontinue if serotonin syndrome develops
May reduce motility of sperm
Advise patient that photosensitivity possible
Advise patient to avoid exposure to direct sunlight

Caution is advised in the treatment of aniline-induced methaemoglobinaemia as the use of methylthioninium chloride may precipitate Heinz body formation and haemolytic anaemia. Lower doses should therefore be considered and total cumulative dose should not exceed 4mg/kg.

Caution is advised in the treatment of dapsone-induced haemolytic anaemia as the use of methylthioninium chloride may exacerbate it. It is recommended not to exceed a cumulative dose for the course of treatment of 4mg/kg in patients with dapsone-induced methylthioninium chloride.

Consider cytochrome b5 reductase deficiency, glucose-6-phosphate dehydrogenase deficiency or sulfhaemoglobinemia if patient fails to respond.

Avoid concomitant use with serotonergic drugs. Where an emergency context demands concomitant administration, monitor patient closely for signs of serotonin syndrome during and for 4 hours after administration.

Check oxygen saturation by co-oximetry when available, as methylthioninium chloride may affect pulse oximetry readings.

Methylthioninium chloride is contraindicated by the manufacturer to treat methaemoglobinaemia caused by sodium nitrite in the treatment of cyanide poisoning. In such cases, the sodium nitrite binding to cyanide will be reduced with resultant increase in the toxicity due to the cyanide. Seek advice from the national poisons information service.

Methylthioninium chloride is contraindicated by the manufacturer to treat methaemoglobinaemia due to chlorate poisoning as there is a risk that more toxic hypochlorite may be produced. Its use may, however, be appropriate in cases of severe chlorate poisoning. Seek advice from the national poisons information service.

Pregnancy and Lactation

Pregnancy

Use methylthioninium chloride with caution in pregnancy.

There is limited published information regarding the use of methylthioninium chloride in pregnancy. Due to its use in an emergency setting, methylthioninium chloride may be used in pregnancy only if the expected benefit outweighs the potential risk. The manufacturer states that it should only be used during pregnancy if clearly necessary.

Animal studies have shown reproductive toxicity.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password at ( https://www.toxbase.org/ ) or if this is unavailable at the backup site ( https://www.TOXBASEbackup.org/ ).

Lactation

Use methylthioninium chloride with caution in breastfeeding.

It is unknown whether methylthioninium chloride is excreted in human milk, and the potential risk to breast-fed infants is therefore unknown. The manufacturer recommends that breastfeeding should be discontinued for up to 8 days after administration.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Agitation
Anaphylactic reaction
Anxiety
Aphasia
Cardiac arrhythmias
Chest pain
Chromaturia
Confusion
Decrease in haemoglobin
Discolouration of stools
Dizziness
Dysgeusia
Dyspnoea
Fever
Haemolysis
Haemolytic anaemia
Headache
Hyperbilirubinaemia
Hypertension
Hypotension
Hypoxia
Local pain (injection site)
Methaemoglobinaemia
Mydriasis
Nausea
Painful extremities
Paraesthesia
Photosensitivity
Precordial pain
Serotonin syndrome
Skin discolouration
Sweating
Tachycardia
Tachypnoea
Tissue damage(injection site)
Tremor
Urticaria
Vomiting

Presentation

Parenteral formulations of methylthioninium chloride.

Drugs List

Therapeutic Indications

Uses

Treatment of drug-induced methaemoglobinaemia

Medicinal and chemical products-induced methaemoglobinaemia.

Dosage

Adults

Children

Patients with Renal Impairment

Administration

For intravenous injection only. The solution should be injected slowly, over a period of 5 minutes in order to prevent high local concentrations of the compound from producing additional methaemoglobin.

The concentrate for solution for injection may be diluted to avoid local pain especially in children. Consult product information.

Contraindications

G6PD deficiency
NADPH-dependent methaemoglobin reductase deficiency
Severe renal impairment

Precautions and Warnings

Children under 3 months
Methaemoglobinaemia due to chlorate poisoning
Nitrite-induced methaemoglobinaemia during treatment of cyanide poisoning
Breastfeeding
Diabetes mellitus
Hyperglycaemia
Moderate renal impairment
Pregnancy
Severe hepatic impairment

Advise ability to drive/operate machinery may be affected by side effects
Administer IV injection slowly
Large dose may cause methaemoglobinaemia - monitor levels closely
Monitor blood pressure and ECG continuously throughout treatment
Monitor haemoglobin levels
Monitor patients for signs and symptoms of Serotonin Syndrome
Advise patient to expect blue-green discolouration of the urine
Discontinue if serotonin syndrome develops
May reduce motility of sperm
Advise patient that photosensitivity possible
Advise patient to avoid exposure to direct sunlight

Caution is advised in the treatment of aniline-induced methaemoglobinaemia as the use of methylthioninium chloride may precipitate Heinz body formation and haemolytic anaemia. Lower doses should therefore be considered and total cumulative dose should not exceed 4mg/kg.

Caution is advised in the treatment of dapsone-induced haemolytic anaemia as the use of methylthioninium chloride may exacerbate it. It is recommended not to exceed a cumulative dose for the course of treatment of 4mg/kg in patients with dapsone-induced methylthioninium chloride.

Consider cytochrome b5 reductase deficiency, glucose-6-phosphate dehydrogenase deficiency or sulfhaemoglobinemia if patient fails to respond.

Avoid concomitant use with serotonergic drugs. Where an emergency context demands concomitant administration, monitor patient closely for signs of serotonin syndrome during and for 4 hours after administration.

Check oxygen saturation by co-oximetry when available, as methylthioninium chloride may affect pulse oximetry readings.

Methylthioninium chloride is contraindicated by the manufacturer to treat methaemoglobinaemia caused by sodium nitrite in the treatment of cyanide poisoning. In such cases, the sodium nitrite binding to cyanide will be reduced with resultant increase in the toxicity due to the cyanide. Seek advice from the national poisons information service.

Methylthioninium chloride is contraindicated by the manufacturer to treat methaemoglobinaemia due to chlorate poisoning as there is a risk that more toxic hypochlorite may be produced. Its use may, however, be appropriate in cases of severe chlorate poisoning. Seek advice from the national poisons information service.

Pregnancy and Lactation

Pregnancy

Use methylthioninium chloride with caution in pregnancy.

There is limited published information regarding the use of methylthioninium chloride in pregnancy. Due to its use in an emergency setting, methylthioninium chloride may be used in pregnancy only if the expected benefit outweighs the potential risk. The manufacturer states that it should only be used during pregnancy if clearly necessary.

Animal studies have shown reproductive toxicity.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password at ( https://www.toxbase.org/ ) or if this is unavailable at the backup site ( https://www.TOXBASEbackup.org/ ).

Lactation

Use methylthioninium chloride with caution in breastfeeding.

It is unknown whether methylthioninium chloride is excreted in human milk, and the potential risk to breast-fed infants is therefore unknown. The manufacturer recommends that breastfeeding should be discontinued for up to 8 days after administration.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Agitation
Anaphylactic reaction
Anxiety
Aphasia
Cardiac arrhythmias
Chest pain
Chromaturia
Confusion
Decrease in haemoglobin
Discolouration of stools
Dizziness
Dysgeusia
Dyspnoea
Fever
Haemolysis
Haemolytic anaemia
Headache
Hyperbilirubinaemia
Hypertension
Hypotension
Hypoxia
Local pain (injection site)
Methaemoglobinaemia
Mydriasis
Nausea
Painful extremities
Paraesthesia
Photosensitivity
Precordial pain
Serotonin syndrome
Skin discolouration
Sweating
Tachycardia
Tachypnoea
Tissue damage(injection site)
Tremor
Urticaria
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review: May 2018

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

MHRA Drug Safety Update April 2009
Available at: https://www.mhra.gov.uk
Last accessed: 17th May 2018

Summary of Product Characteristics: Methylthioninium chloride Proveblue 5mg/ml solution for injection. Martindale Pharma. Revised February 2018.

Summary of Product Characteristics: Methylthioninium chloride 10mg/ml concentration for solution for injection. Flexipharm Austrading Limited. Revised September 2019.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 9th May 2018