Skip to content
ClinCalc Pro
Menu
Calculators Drugs Pathways AI Dx Donate Get the App
Guanylate Cyclase / Nitric Oxide Pathway Inhibitor Pregnancy: There are no adequate data from the use of methylthioninium chloride in pregnant women. Studies in animals have shown reproductive toxicity; the potential risk for humans is unknown. 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 and 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. Fertility: in vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dose dependent manner.

Methylene Blue

Brand names: Provayblue, Methylthioninium chloride

Methylene blue (methylthioninium chloride) is an intravenous agent used in critical care as a rescue vasopressor in refractory vasoplegic/distributive shock and as the antidote for acquired methaemoglobinaemia.

Adult dose

Dose: Acute symptomatic methaemoglobinaemia: 1 to 2 mg/kg body weight (equivalent to 0.2-0.4 ml/kg of the 5 mg/ml solution), given over a period of 5 minutes
Route: Intravenous use. Must be injected very slowly over a period of 5 minutes. 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 the paediatric population. It must NOT be administered by subcutaneous or intrathecal injection
Frequency: A repeat dose (1 to 2 mg/kg body weight, i.e. 0.2-0.4 ml/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. Treatment does not usually exceed one day
Max: 7 mg/kg cumulative for the course of treatment. SPC wording: '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 aniline- or dapsone-induced methaemoglobinaemia the maximum recommended cumulative dose for the course of treatment is 4 mg/kg
SCOPE - THIS DRAFT COVERS THE LICENSED INDICATION OF THE FETCHED PRODUCT ONLY: intravenous methylthioninium chloride for acute symptomatic methaemoglobinaemia. NOT COVERED BY THIS SOURCE: vasoplegic shock / vasoplegia and ifosfamide-induced encephalopathy - the two off-label ICU uses implied by this page's category label ('Guanylate Cyclase / Nitric Oxide Pathway Inhibitor'). No regimen for either appears anywhere in this SPC; do not infer one from the methaemoglobinaemia figures above. CONTINUOUS INFUSION, verbatim: 'Too limited data are available to support a continuous infusion dose recommendation.' RENAL IMPAIRMENT (infants above 3 months, children, adolescents and adults): moderate impairment (eGFR 30-59 ml/min/1.73 m2) 1-2 mg/kg, and if a 1 mg/kg dose is given a repeat 1 mg/kg may be given one hour later, with a maximum cumulative dose for the course of 2 mg/kg; severe impairment (eGFR 15-29 ml/min/1.73 m2) a single dose of 1 mg/kg with a maximum cumulative dose for the course of 1 mg/kg; no dose adjustment in mild impairment (eGFR 60-89 ml/min/1.73 m2). Safety and efficacy in end stage renal disease, with or without dialysis, has not been established. HEPATIC IMPAIRMENT: safety and efficacy not established, no data available. ELDERLY: no dose adjustment is necessary. ADMINISTRATION BY A HEALTHCARE PROFESSIONAL: 'Methylthioninium chloride Proveblue is for administration by a healthcare professional.'

Paediatric dose

Dose: 1 mg/kg
Route: Intravenous, injected very slowly over a period of 5 minutes; may be diluted in 50 ml glucose 50 mg/ml (5%) solution for injection to avoid local pain, in particular in the paediatric population
Frequency: A repeat dose 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
Max: 7 mg/kg cumulative for the course of treatment (4 mg/kg in aniline- or dapsone-induced methaemoglobinaemia)
Concentration: 5 mg/ml
dosePerKg is a PER-DOSE value, not a daily total. The figure shown (1 mg/kg) is the lower bound of the SPC's paediatric range for infants above 3 months, children and adolescents, whose posology is stated verbatim as 'Same posology as for adults', i.e. 1 to 2 mg/kg body weight (0.2-0.4 ml/kg) over 5 minutes. NEONATES AND YOUNG INFANTS - A DIFFERENT, LOWER DOSE APPLIES: for infants 3 months old or younger and newborn infants the recommended dose is 0.3-0.5 mg/kg body weight (0.06 to 0.1 ml/kg) given over a period of 5 minutes, with a repeat dose of 0.3-0.5 mg/kg permitted one hour after the first dose on the same criteria. Do not apply the 1-2 mg/kg figure to this age group. RENAL IMPAIRMENT IN THE VERY YOUNG, verbatim: '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.'

Dose independently re-sourced from UK Summary of Product Characteristics (SPC) via the eMC — clinician-reviewed. Always confirm against the product SmPC and your local formulary before prescribing.

Paediatric weight-based calculator

dosePerKg is a PER-DOSE value, not a daily total. The figure shown (1 mg/kg) is the lower bound of the SPC's paediatric range for infants above 3 months, children and adolescents, whose posology is stated verbatim as 'Same posology as for adults', i.e. 1 to 2 mg/kg body weight (0.2-0.4 ml/kg) over 5 minutes. NEONATES AND YOUNG INFANTS - A DIFFERENT, LOWER DOSE APPLIES: for infants 3 months old or younger and newborn infants the recommended dose is 0.3-0.5 mg/kg body weight (0.06 to 0.1 ml/kg) given over a period of 5 minutes, with a repeat dose of 0.3-0.5 mg/kg permitted one hour after the first dose on the same criteria. Do not apply the 1-2 mg/kg figure to this age group. RENAL IMPAIRMENT IN THE VERY YOUNG, verbatim: '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.'

Verify in a children's formulary

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

Side effects

  • Dizziness (very common)
  • Paraesthesia (very common)
  • Dysgeusia (very common)
  • Nausea (very common)
  • Headache, anxiety, vomiting, abdominal pain (common)
  • Hypotension and cardiac arrhythmias - intravenous injection of methylthioninium chloride has occasionally caused these, and such disorders might prove fatal on rare occasions
  • Methaemoglobinaemia, hyperbilirubinaemia and haemolytic anaemia (frequency not known)
  • Anaphylactic reactions (frequency not known)
  • Serotonin syndrome with concomitant use of serotonergic drugs (frequency not known)
  • Skin discoloration (blue), chromaturia and blue-green discoloration of faeces
  • Injection site pain and pain in extremity
  • Confusional state, agitation, tremor, fever, aphasia, mydriasis, tachycardia, hypertension, dyspnoea, tachypnoea, hypoxia (frequency not known)

Monitoring

  • Electrocardiogram (ECG) and blood pressure should be monitored during and after treatment, as hypotension and cardiac arrhythmia are potential adverse reactions
  • In cases of suspected methaemoglobinaemia, 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
  • Methaemoglobin levels - used in the SPC as the criterion for a repeat dose at one hour
  • Watch for exacerbation of Heinz body formation and haemolytic anaemia; lower doses should be considered and the total cumulative dose should not exceed 4 mg/kg in that setting
  • Anaesthetists should be vigilant for methaemoglobinaemia in patients receiving dapsone therapy, and for BIS (Bispectral Index) interference during administration
  • Failure to respond suggests cytochrome b5 reductase deficiency, glucose-6-phosphate dehydrogenase deficiency or sulfhaemoglobinaemia - alternative treatment options should be considered
  • Avoid concomitant use with selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors - risk of serious or fatal serotonergic syndrome
  • Note that the product imparts a blue-green colour to urine and faeces and a blue colour to skin, which may hinder a diagnosis of cyanosis

Clinical monograph

How it works

It inhibits guanylate cyclase and nitric oxide synthase, reducing cyclic GMP-mediated vasodilatation to restore vascular tone; in methaemoglobinaemia it acts via NADPH-dependent reduction to convert methaemoglobin back to functional haemoglobin.

Prescribing in practice

  • It is a potent serotonergic agent and can precipitate serotonin syndrome when combined with serotonergic drugs such as SSRIs, SNRIs and MAOIs, which should be reviewed before administration.
  • It is contraindicated or hazardous in glucose-6-phosphate dehydrogenase deficiency, where it is ineffective for methaemoglobinaemia and may cause haemolysis.
  • It transiently interferes with pulse oximetry readings and discolours urine blue-green; give slowly intravenously as it can itself cause methaemoglobinaemia at high cumulative doses.

Monitoring

Monitor blood pressure, oxygenation (recognising pulse oximetry interference) and, where relevant, methaemoglobin levels and for signs of serotonin toxicity.

Counselling the patient

  • This medicine may turn the urine a blue-green colour, which is harmless and expected.
  • The team will review all other medicines first because of an interaction risk with certain antidepressants.
  • Oxygen saturation readings may read inaccurately for a short time after it is given.

Evidence & guidelines

Methylene blue is the established first-line treatment for acquired methaemoglobinaemia and is used as adjunctive rescue therapy in refractory vasoplegia; MHRA advises caution because of its serotonergic interaction potential.

Reference: MHRA Drug Safety Update 2012 (serotonin syndrome); TOXBASE NPIS (methaemoglobinaemia); Methylene Blue in Vasoplegic Shock — Systematic Review (Belletti et al. 2018); MHRA SPC Provayblue; Drug verified in RxNorm (NLM); confirm dosing against the manufacturer SPC (eMC). Verify against your local formulary and current prescribing references before prescribing. The structured dose values shown have been reviewed by a clinician. Monograph status: clinician-reviewed (2026-07-04).

Related

Curated clinical cross-links plus same-class fallbacks.

Calculators