SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methylthioninium Chloride EmBlue 10 mg/ml Concentrate for Solution for Injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate for solution for injection contains 10 mg Methylthioninium Chloride (trihydrate).

Each 5 ml vial contains 50 mg of Methylthioninium Chloride (trihydrate).

For excipients, see 6.1

3    PHARMACEUTICAL FORM

Concentrate for solution for injection A clear, blue coloured sterile solution

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Methylthioninium Chloride EmBlue is primarily used in the treatment of drug-induced and genetic methaemoglobinaemia that are not due to a structural abnormality of haemoglobin.

4.2    Posology and method of administration

Methylthioninium Chloride EmBlue may be administered orally or by intravenous (IV) injection. In the treatment of acute methaemoglobinaemia, the IV route of administration is usually preferred because it provides a more rapid onset of effect. However, in large doses, Methylthioninium Chloride can itself produce methaemoglobinaemia and the methaemoglobin concentration should therefore be closely monitored during treatment. The usual IV dose of Methylthioninium Chloride EmBlue for adults and children is as a 1% solution in doses of 1 to 2 mg/kg bodyweight injected over a period of several minutes. A repeat dose may be given after one hour if required.

When treatment is less urgent, and for chronic dosing of genetic methaemoglobinaemia, Methylthioninium Chloride EmBlue 3-6 mg/kg (generally 300 mg daily in adults) is given orally in divided doses over 24 hours with ascorbic acid 500 mg daily. A suitable dilution for oral dosing would be 5-10 ml of the 1% solution diluted to 100-200 ml with water for injection. The high volume is suggested to reduce the degree of gastrointestinal disturbance and dysuria.

The dosage of Methylthioninium Chloride should be calculated on the basis of lean bodyweight.

4.3    Contraindications

Use of Methylthioninium Chloride in pregnancy and lactation is contraindicated as its safe use during pregnancy has not yet been established.

Methylthioninium Chloride is contraindicated in patients with severe renal impairment or a known hypersensitivity to the drug.

Methylthioninium Chloride should not be used for the treatment of methaemoglobinaemia due to chlorate poisoning as it may convert the chlorate to hypochlorite which is an even more toxic compound.

Methylthioninium Chloride may cause haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Intrathecal injection of Methylthioninium Chloride can result in neural damage and is therefore contraindicated.

4.4    Special warnings and precautions for use

Long term administration of Methylthioninium Chloride may result in marked anaemia due to accelerated destruction of erythrocytes; haemoglobin concentrations should be checked frequently.

If Methylthioninium Chloride is injected subcutaneously or if extravasation occurs, necrotic abscesses may result.

4.5    Interaction with other medicinal products and other forms of interaction

No information available.

4.6    Fertility, pregnancy and lactation

Use in Pregnancy

Safe use of Methylthioninium Chloride during pregnancy has not been established. Therefore, the drug should be used in pregnant women only if clearly indicated.

Although intra-amniotic injection of Methylthioninium Chloride has been used to diagnose premature rupture of foetal membranes or to identify separate amniotic sacs in twin pregnancies, there have been several reports of haemolytic anaemia and hyperbilirubinaemia in neonates exposed to Methylthioninium Chloride in the amniotic cavity.

Use in Lactation

There is no information on whether or not the drug crosses into the breast milk. Consequently, the potential hazard to the infant must be considered prior to administration of the drug to nursing mothers.

4.7    Effects on ability to drive and use machines

None.

4.8    Undesirable effects

After intravenous administration, Methylthioninium Chloride may cause nausea, vomiting, abdominal and chest pain, headache, dizziness, mental confusion, profuse sweating and hypotension; with very high doses methaemoglobinaemia and haemolysis may occur. Infants and patients with glucose-6-phosphate dehydrogenase deficiency are particularly susceptible to haemolysis from treatment with Methylthioninium Chloride.

Oral administration may cause gastrointestinal disturbances (nausea, vomiting and diarrhoea) and dysuria.

High doses, if not adequately diluted, could cause thrombophlebitis. Not more than 350 mg of Methylthioninium Chloride should be diluted in each 500 ml of infusion fluid.

Methylthioninium Chloride imparts a blue colour to the saliva, urine and faeces.

4.9 Overdose

No specific information is available. However, in high concentrations, Methylthioninium Chloride can oxidize haemoglobin to methaemoglobinemia, thus increasing methaemoglobinemia. Nonspecific side effects seen with high doses included precordial pain, dyspnea, restlessness, apprehension, tremors, and a sense of oppression. Large doses are irritant to the urinary tract. In addition, it can produce a mild haemolysis with moderate hyper bilrubinemia, reticulosis and slight anaemia. Rarely, however, a severe haemolytic anaemia with Heinz body formation has resulted. Methylthioninium Chloride in large doses could cause a blue discolouration to the skin after methaemoglobin levels had returned to normal.

Treatment of Overdosage

General supportive care and removal of the toxin should be carried out. Depending on the severity of the poisoning and the etiologic agent, this may include removal of contaminated clothing, rinsing the skin with water, ipecac-induced emesis or gastric lavage, charcoal, cathartics, and even haemodialysis.

There is no specific antidotal therapy. Although in severe and refractory cases methaemoglobinemia, blood transfusions and even exchange transfusions, and (possibly) hyperbolic oxygen therapy maybe the only alternative available. Ascorbic acid works slowly and is probably no benefit in the acute situation. Removal of the toxic compound and supportive therapy are essential.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

In patients with methaemoglobinemia, therapeutic doses of Methylthioninium Chloride can lower the levels of methaemoglobin in the red blood cells. It activates a normally dormant reductase enzyme system which reduces the Methylthioninium Chloride to leucomethylthioninium chloride, which in turn is able to reduce methaemoglobin to haemoglobin. However, in large doses, Methylthioninium Chloride can itself produce methaemoglobinemia and the methaemglobin concentration should therefore be closely monitored during treatment. Methylthioninium Chloride is not effective for the treatment of methaemoglobinemia in patients with glucose-6-phosphate dehydrogenase deficiency as these patients have a diminished capacity to reduce Methylthioninium Chloride to leucomethylthioninium chloride. It is also potentially harmful as patients with glucose-6-phosphate dehydrogenase deficiency are particularly susceptible to the haemolytic anaemias induced by Methylthioninium Chloride.

Methylthioninium Chloride also possesses weak antiseptic and bacteriological staining properties and is reported to inhibit amine oxidase in tissues. The drug appears to bind irreversibly to viral nucleic acid and cause disruption of the virus molecule upon exposure to light.

5.2 Pharmacokinetic properties

Methylthioninium Chloride is well absorbed from the human gastrointestinal tract and is rapidly reduced to leucomethylthioninium chloride.

About 75% of a single 10 mg oral dose of Methylthioninium Chloride is recovered from the urine, mainly (80%) as leucomethylthioninium chloride. This metabolite is colourless but turns green or blue on exposure to air due to presence of the oxidation product methylene azure (methylthioninium chloride sulphone).

5.3 Preclinical safety data

None

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Water for Injections

6.2    Incompatibilities

Methylthioninium Chloride is reported to be incompatible with caustic alkalis, iodides, dichromates and oxidising and reducing substances.

6.3 Shelf life

Prior to first use: 36 months. In use: 24 hours

6.4 Special precautions for storage

Prior to first use:    Do not store above 25°C

In use: Following dilution in either 0.9% sodium chloride or 5% dextrose solution, chemical and physical in-use stability has been demonstrated for 24 hours at temperature not above 25 °C.

However, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer

than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.5    Nature and contents of container

50 mg/5ml- Clear Type I glass ampoule in packs of 5 ampoules.

6.6    Special precautions for disposal

For single use.

Discard any unused contents.

7. MARKETING AUTHORISATION HOLDER

EmBlue Limited Ternion Court,

264-268 Upper Fourth Street,

Central Milton Keynes,

Buckinghamshire,

MK9 1DP,

UK.

8.    MARKETING AUTHORISATION NUMBER(S)

PL 42973/0001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

17/12/1993

10 DATE OF REVISION OF THE TEXT

27/04/2015