Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: PROVEPHARM SAS, 22 rue Marc Donadille, 13013, Marseille, France
Pharmacotherapeutic group: All other therapeutic products, antidotes
ATC code: V03AB17
In vivo, in low concentration, methylthioninium chloride speeds up the conversion of methaemoglobin to haemoglobin.
Methylthioninium chloride Proveblue has been observed to stain tissues selectively. Its use in parathyroid surgery (not indicated) has induced adverse CNS effects when administered concomitantly with serotonergic medicinal products (see section 4.5).
The efficacy of methylthioninium chloride for the treatment of methaemoglobinaemia in peadiatric population was demonstrated in two retrospective studies and one open randomised clinical trial. Case reports of efficacy are also available in literature. Please refer to section 4.4 for important safety information.
After intravenous administration Methylthioninium chloride Proveblue is rapidly taken up by the tissues. It is also well absorbed by the oral route. The majority of the dose is excreted in the urine, usually in the form of leucomethylthioninium chloride.
The estimated terminal half-life of methylthioninium chloride after intravenous administration is 26.7h.
Methylthioninium chloride Proveblue is not an in vitro inducer of CYP2B6 and CYP3A4.
Methylthioninium chloride Proveblue is an in vitro inhibitor of P-gp.
Methylthioninium chloride Proveblue is not an in vitro substrate for BCRP or OCT2 and is not an in vitro inhibitor of BCRP, OAT1 or OAT3.
One-month repeated dose toxicity in dogs showed no macroscopic toxic effects. Adverse reactions, seen at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were moderate regenerative anaemia associated with increased mean platelet count and fibrinogen levels, a minimal increase in mean total bilirubin blood values and an increased incidence of moderate urine bilirubin levels.
Methylthioninium chloride was mutagenic in gene mutation assays in bacteria and mouse lymphoma cells but not in vivo mouse micronucleus assay when administered intravenously at 62 mg/kg.
Some evidence of carcinogenic activity of methylthioniniul chloride has been shown in male mice and male rats. An equivocal evidence of carcinogenic activity was observed in female mice. No evidence of carcinogenic activity was observed in female rats.
In vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dose dependant manner. It has also been shown to inhibit the growth of cultured two-cell mouse embryos and the production of progesterone in cultured human luteal cells. In rats and rabbits, teratogenic effects have been reported, with foetal and maternal toxicity. In rats, increased resorption rates have been observed.
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