Methylthioninium chloride Other names: Methylene blue

Methylthioninium chloride may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use of methylthioninium chloride with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors.

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.

Methylthioninium chloride should be avoided in patients receiving medicinal products that enhance serotonergic transmission because of the potential for serious CNS reactions, including potentially fatal serotonin syndrome. These include SSRIs (selective serotonin reuptake inhibitors), bupropion, buspirone, clomipramine, mirtazapine, and venlafaxine. If the intravenous use of methylthioninium chloride cannot be avoided in patients treated with serotonergic medicinal products, the lowest possible dose should be chosen and the patient observed closely for central nervous system (CNS) effects for up to 4 hours after administration.

Methylthioninium chloride is an in vitro inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. The clinical consequences of increases plasma concentration of co-administered drugs which are sensitive CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A substrates cannot be ruled out.

Methylthioninium chloride is an in vitro inducer of CYP1A2. The clinical consequence is not known.

The administration of methylthioninium chloride Proveblue has the potential to transiently increase or decrease the clearance of drugs that are primarily metabolized by these enzymes. The clinical consequences are however considered minimal since methylthioninium chloride is used often only once and in an acute emergency setting.

In vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dose dependant manner.

Methylthioninium chloride is a potent inhibitor of the transporters OCT2, MATE1 and MATE2-K. The clinical consequences of the inhibition are not known. The administration of methylthioninium chloride Proveblue has the potential to transiently increase the exposure of drugs primarily cleared by renal transport involving the OCT2/MATE pathway, including cimetidine, metformin and acyclovir.

Methylthioninium chloride 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.

Anaesthesiologists should be vigilant for methaemoglobinaemia in patients receiving dapsone therapy and for BIS (Bispectral Index) interference with methylthioninium chloride administration.

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.

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. Methylthioninium chloride Proveblue should not be used during pregnancy unless clearly necessary, e.g. in life-threatening methaemoglobinaemia.

It is unknown whether methylthioninium chloride is excreted in human breast milk. The excretion of methylthioninium chloride in milk has not been studied in animals. 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 with methylthioninium chloride.

In vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dose dependant manner.

Methylthioninium chloride has moderate influence on the ability to drive and use machines. Indeed, driving can be affected due to confusional state, dizziness and possibly eye disturbances. However, the risk is limited as the medicinal product is intended for acute administration only in emergency situations at hospital.

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.

List of adverse reactions

The adverse reactions listed 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.

Blood and lymphatic system disorders

Not known: Methaemoglobinaemia, Hyperbilirubinaemia¹, Haemolytic anaemia

Immune system disorders

Not known: Anaphylactic reactions

Psychiatric disorders

Not known: Confusional state, Agitation

Nervous system disorders

Very common: Dizziness

Common: Headache, Anxiety

Not known: Tremor, Fever, Aphasia

Very common: Paraesthesia, Dysgeusia

Not known: Serotonin Syndrome with concomitant use of serotonergic drugs

Eye disorders

Not known: Mydriasis

Cardiac disorders

Not known: Cardiac arrhythmia, Tachycardia

Vascular disorders

Not known: Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders

Not known: Dyspnoea, Tachypnoea, Hypoxia

Gastrointestinal disorders

Very common: Nausea

Common: Vomiting, Abdominal pain

Not known: Faeces discoloration (blue-green)

Skin and subcutaneous tissue disorders

Very common: Skin discoloration (blue), Sweating

Not known: Urticaria, Phototoxicity/Photosensitivity

Renal and urinary disorders

Very common: Chromaturia (blue-green)

General disorders and administration site conditions

Common: Chest pain, Injection site pain

Not known: Local tissue necrosis at the injection site

Investigations

Not known: Haemoglobin decreased

Musculoskeletal and connective tissue disorder

Very common: Pain in extremity

Paediatric population

Adverse reactions are the same as in adults (except hyperbilirubinaemia, reported in infants only).