Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: PROVEPHARM SAS, 22 rue Marc Donadille, 13013, Marseille, France
Acute symptomatic treatment of medicinal and chemical products-induced methaemoglobinaemia.
Methylthioninium chloride Proveblue is indicated in adults, children and adolescents (aged 0 to 17 years old).
Methylthioninium chloride Proveblue is for administration by a healthcare professional.
The usual dose is 1 to 2 mg per kg body weight, i.e. 0.2-0.4 ml per kg body weight, given over a period of 5 minutes.
A repeat dose (1 to 2 mg/kg body weight, i.e. 0.2-0.4 ml/kg body weight) 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.
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 the case of aniline- or dapsone-induced methaemaglobinaemia, the maximum recommended cumulative dose for the course of treatment is 4 mg/kg (see section 4.4).
Too limited data are available to support a continuous infusion dose recommendation.
No dose adjustment is necessary.
Methylthioninium chloride should be used with caution in patients with moderate to severe renal disease since there is limited data available and methylthioninium chloride is predominantly renally eliminated. Lower doses (<1 mg/kg) may be needed. Hepatic impairment There is no experience in patients with severe hepatic impairment.
Infants above 3 months, children and adolescents: Same posology as for adults.
Infants 3 months old or younger and newborn infants: The recommended dose is 0.3-0.5 mg/kg body weight, i.e. 0.06 to 0.1 ml/kg body weight, given over a period of 5 minutes.
A repeat dose (0.3 to 0.5 mg/kg body weight, i.e. 0.06-0.1 ml/kg body weight) 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 (see section 4.4 for important safety information).
Treatment does not usually exceed one day.
For intravenous use.
Methylthioninium chloride 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 paediatric population.
It must be injected very slowly over a period of 5 minutes.
It must not be administered by subcutaneous or intrathecal injection.
For instructions on handling and dilution of the medicinal product before administration, see section 6.6.
The administration of large intravenous doses (≥7 mg/kg) of Methylthioninium chloride Proveblue to individuals without methaemoglobinaemia induces nausea and vomiting, chest tightness, chest pain, tachycardia, apprehension, severe sweating, tremor, mydriasis, blue-green staining of the urine, blue staining of the skin and mucous membranes, abdominal pain, dizziness, paraesthesia, headache, confusion, hypertension, mild methaemoglobinaemia (up to 7%) and electrocardiogram changes (T wave flattening or inversion). These features resolve generally within 2-12 hours of the injection.
Cumulative doses of Methylthioninium chloride may lead to dyspnoea and tachypnoea, presumably related to reduced oxygen availability caused by methaemoglobinaemia, chest pain, tremor, cyanosis and haemolytic anaemia.
Haemolytic anaemia has also been reported in case of severe overdose (20-30 mg/kg) in infants and adults with methaemoglobinaemia caused by aniline or chlorates. Haemodialysis may be used in patients with severe haemolysis.
Hyperbilirubinaemia has been observed in infants after administration of 20 mg/kg methylthioninium chloride.
Death occurred in 2 infants after administration of 20 mg/kg methylthioninium chloride. Both infants had complex medical circumstances and methylthioninium chloride was only partially responsible.
The patient should be maintained under observation, the methaemoglobin level should be monitored and appropriate supportive measures taken as necessary.
Shelf life: 3 years.
After opening or dilution: From a microbiological point of view, unless the method of opening/dilution precludes the risk of microbial contamination, the product must be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
Do not refrigerate or freeze.
Keep the ampoule in the original package in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
Type I glass ampoules.
Each carton contains a tray with 5 ampoules of 10 ml in blister.
Each carton contains a tray with 5 or 20 ampoules of 2 ml in blister.
Not all pack sizes may be marketed.
For single use only.
Methylthioninium chloride Proveblue may be diluted in 50 ml glucose 50 mg/ml (5%) solution for injection to avoid local pain, in particular in paediatric population. Before any administration, it is recommended to inspect the parenteral solutions to verify that they are free of particles. Do not use Methylthioninium chloride Proveblue if the solution is discoloured, cloudy, turbid, or a precipitate or particles are present.
Any unused product or waste material should be disposed of in accordance with local requirements.
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