METHYLTHIONINIUM CHLORIDE PROVEBLUE Solution for injection Ref.[8668] Active ingredients: Methylthioninium chloride

General

Methylthioninium chloride Proveblue must be injected very slowly over a period of 5 minutes to prevent high local concentrations of the compound from producing additional methaemoglobin.

It imparts a blue-green colour to urine, 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 Proveblue 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.

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.

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

Electrocardiogram (ECG) and blood pressure should be monitored during and after treatment with Methylthioninium chloride Proveblue as hypotension and cardiac arrhythmia are potential adverse reactions (see section 4.8).

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. Avoid concomitant use of methylthioninium chloride with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (see section 4.5).

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.

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 (see sections 4.4 and 4.8).

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 Proveblue is used often only once and in an acute emergency setting.

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 is a substrate of P-glycoprotein (P-gp). The clinical consequences are considered likely to be minimal due to the transient and single dose use that normally occurs in the emergency setting.

Pregnancy

There are no adequate data from the use of methylthioninium chloride in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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.

Breast-feeding

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 Proveblue.

Fertility

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.

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.

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 (see section 4.4 and section 4.5).

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).

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. It must especially not be mixed with sodium chloride 9 mg/ml (0.9%) solution for injection because it has been demonstrated that chloride reduces the solubility of methylthioninium chloride.