Adult: As 0.5% or 1% solution: 1-2 mg/kg via slow inj over a period of 5 minutes, may be repeated after 30-60 minutes if necessary. Max total dose: 7 mg/kg per treatment course; 4 mg/kg per treatment course (aniline- or dapsone-induced methaemoglobinaemia). Child: As 0.5% solution: Newborn to 3 months infants 0.3-0.5 mg/kg via slow inj over 5 minutes, may be repeated after 60 minutes if necessary. >3 months Same as adult dose.
Oral Acute methaemoglobinaemia
Adult: Dilute 10-20 mL of 0.5% solution for inj with 100-200 mL water for inj.
Special Patient Group
Pharmacogenomics:
G6PD deficiency is an X-linked genetic variant wherein women may either be homozygous or heterozygous for the variant, while men may be hemizygous. Based on studies, several cases of haemolytic anaemia were reported in individuals of various ethnicities after exposure to IV methylthioninium chloride. Most, but not all, were tested and identified to be G6PD deficient.
Drug labels (as approved by FDA, EMA and PMDA) for methylthioninium chloride states that it is contraindicated in patients with G6PD deficiency due to the risk of haemolytic anaemia. Methylthioninium chloride may be ineffective for the treatment of methaemoglobinaemia in G6PD deficient patients due to their inability to reduce the drug to its active form. Furthermore, EMA and PMDA approved drug labels also states that methylthioninium chloride is contraindicated in patients with a deficiency in NADPH reductase (encoded by BLVRB gene).
Individuals who failed to respond to methylthioninium chloride may indicate a deficiency in cytochrome b5 reductase (CYPB5R3) or G6PD. Consider alternative treatment options.
Reconstitution
May be diluted with 50 mL of 5% dextrose in water prior to administration.
Incompatibility
Reduced solubility with 0.9% NaCl solution for inj.
Contraindications
Hypersensitivity to methylthioninium chloride or other thiazine dyes. G6PD deficiency, NADPH reductase deficiency, nitrite-induced methaemoglobinaemia during treatment of cyanide poisoning, chlorate-induced methaemoglobinaemia. Pregnancy and lactation.
Special Precautions
Patients with hyperglycaemia or diabetes mellitus. Not intended to be administered via SC or intraspinal inj. Hepatic and renal impairment. Children; newborn and infants (<3 months).
Adverse Reactions
Significant: Hypersensitivity; haemolytic anaemia, methaemoglobinaemia (at high doses or in G6PD deficient patients), CNS depression, cutaneous photosensitivity reaction, skin and body fluid discolouration (blue: skin, blue green: urine, faeces). Cardiac disorders: Chest pain, tachycardia, cardiac arrhythmia. Eye disorders: Mydriasis. Gastrointestinal disorders: Nausea, vomiting, abdominal pain, dysgeusia. General disorders and administration site conditions: Inj site pain or necrosis, fever. Investigations: Hb decreased. Metabolism and nutrition disorders: Hyperbilirubinaemia. Musculoskeletal and connective tissue disorders: Pain in extremity. Nervous system disorders: Dizziness, headache, paraesthesia, tremor. Psychiatric disorders: Anxiety, confusional state, agitation, aphasia. Respiratory, thoracic and mediastinal disorders: Dyspnoea, tachypnoea. Skin and subcutaneous tissue disorders: Hyperhidrosis. Vascular disorders: Hypertension, hypotension. Potentially Fatal: Serotonin syndrome (in combination with serotonergic drugs).
Symptoms: Patients without methaemoglobinaemia: Nausea, vomiting, chest pain, tachycardia, apprehension, severe sweating, tremor, mydriasis; skin, mucous membrane and urine discolouration (blue-green), abdominal pain, dizziness, paraesthesia, headache, confusion, hypertension, ECG changes (T wave flattening or inversion), and mild methaemoglobinaemia. Patients with methaemoglobinaemia: Dyspnoea, tachypnoea, chest pain, tremor, cyanosis, and haemolytic anaemia. Management: Symptomatic and supportive treatment.
Drug Interactions
May increase plasma concentrations of sensitive CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 substrates. May transiently increase exposure of cimetidine, metformin, aciclovir. Potentially Fatal: Increased risk of serotonin syndrome with SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), MAOIs, bupropion, buspirone, clomipramine, mirtazapine.
Lab Interference
May result to underestimation of the oxygen saturation reading in pulse oximetry. May cause false-positive result in phenolsulfonphthalein excretion test. May interfere with the bispectral index values and in the interpretation of urine tests relying on blue indicator (e.g. dipstick for leucocyte esterase).
Action
Description: Methylthioninium chloride, a thiazine dye and oxidation-reduction agent, accelerates the conversion of methaemoglobin to haemoglobin (Hb) in low concentrations. In situ, nicotinamide adenine dinucleotide phosphate (NADPH) reductase converts the methylthioninium chloride into leucomethylthioninium chloride which then reduces the ferric iron of methaemoglobin to the ferrous state of the normal Hb. Synonym: Methylene blue Onset: Reduction of methaemoglobin: 30-60 minutes (IV). Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 1-2 hours (oral); 30 minutes (IV). Distribution: Extensively distributed in the tissues. Volume of distribution 255 L (±58 L). Plasma protein binding: 94%. Metabolism: Undergoes first-pass metabolism or distribution in the tissues via peripheral reduction to form leucomethylene blue. Excretion: Mainly via urine as leucomethylene blue, with small proportion as unchanged drug; bile. Elimination half-life: Approx 5-6.5 hours.
Chemical Structure
Methylthioninium chloride Source: National Center for Biotechnology Information. PubChem Database. Methylene blue, CID=6099, https://pubchem.ncbi.nlm.nih.gov/compound/Methylene-blue (accessed on Jan. 22, 2020)
Storage
Store between 20-25°C. Do not refrigerate or freeze. Protect from light.
V03AB17 - methylthioninium chloride ; Belongs to the class of antidotes. Used in the management of prilocaine overdose.
References
Annotation of EMA Label for Methylene Blue and BLVRB, CYB5R3, G6PD. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 05/11/2019.Annotation of FDA Label for Methylene Blue and G6PD. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 05/11/2019.Annotation of PMDA Label for Methylene Blue and BLVRB, G6PD. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 05/11/2019.Anon. G6PD - Methylene Blue (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/11/2019.Anon. Methylene Blue. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 05/11/2019.Anon. Methylene Blue. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/11/2019.Buckingham R (ed). Methylthioninium Chloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/11/2019.Joint Formulary Committee. Methylthioninium Chloride. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/11/2019.Methylthioninium Chloride 10 mg/mL Sterile Concentrate for Solution for Injection (Phebra Limited). MHRA. https://products.mhra.gov.uk/. Accessed 15/11/2019.Provayblue Injection (American Reagent, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 05/11/2019.
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