methylthioninium chloride: prescribing information – dosing, contraindications, interactions, side effects

Lumeblue is indicated as a diagnostic agent enhancing visualisation of colorectal lesions in adult patients undergoing screening or surveillance colonoscopy (see section 5.1).

Posology

Adults including the elderly (≥ 65 years)

The recommended total dose is 200 mg methylthioninium chloride, corresponding to eight 25 mg tablets.

The total dose of the medicinal product must be taken orally during or after the intake of low-volume (e.g. 2 L) or high-volume (e.g. 4 L) polyethylene glycol (PEG) based bowel cleansing preparation and should be completed the evening prior to the colonoscopy to ensure there is enough time for the tablets to reach the colon and locally release the methylthioninium chloride prior to the colonoscopy.

Special populations

Elderly

No dose adjustment is required for elderly patients (aged ≥ 65 years) (see section 5.2).

Renal impairment

No dose adjustment is required in patients with mild renal impairment. The medicinal product should be used with caution in patients with moderate to severe renal impairment as there are no data in this patient group and methylthioninium chloride is predominantly renally eliminated (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. There is no experience in patients with severe hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of the medicinal product in children aged less than 18 years have not been established. No data are available.

Method of administration

For oral use.

Tablets should be swallowed whole, without crushing, breaking or chewing. The tablets are coated with a gastro-resistant film that facilitates the delivery of the dye into the colon. Breaking the gastro- resistant film by crushing or chewing the tablets may cause early release of the dye in the upper part of the gastrointestinal tract, with a possible loss of the treatment effectiveness.

The patient should take the medicinal product with the low-volume (e.g. 2 L) or high-volume (e.g.
4 L) PEG based bowel cleansing regimen chosen by the healthcare provider according to the dosing schedule below:
- The first dose of 3 tablets should be taken after drinking at least 1 L of the bowel cleansing preparation;
- The second dose of 3 tablets should be taken 1 hour after the first dose;
- The last dose of 2 tablets should be taken 1 hour after the second dose.

Tablets should be taken orally with the bowel cleansing preparation chosen by the healthcare provider or with equivalent water volumes and the proposed dosing schedule is compatible with either full dose or split dose bowel preparations.

• Hypersensitivity to the active substance, peanut or soya, or to any of the excipients listed in section 6.1;
• Patients with known glucose-6-phosphate dehydrogenase (G6PD) deficiency;
• Pregnancy and lactation (see section 4.6).

Summary of safety profile

Lumeblue commonly causes chromaturia (32.4%) and discoloured faeces (13.4%), which gradually diminish over the following days. It is associated with transient nausea and vomiting.

Tabulated list of adverse reactions

Adverse reactions are classified according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Data presented below are based upon clinical studies conducted with Lumeblue. All adverse reactions recorded at a frequency greater than placebo are reported. Additionally, adverse drug reactions of known frequency, reported with methylthioninium chloride administered intravenously in the treatment of methaemoglobinaemia are included in the following table.

System organ class
Adverse reaction
Frequency
Infections and infestations
Nasopharyngitis
Uncommon
Immune system disorders
Anaphylactic reactiona
Not known
Nervous system disorders
Dizzinessb
Very common
Dysgeusiab
Very common
Paraesthesiab
Very common
Anxietyb
Common
Headacheb
Common
Migraine
Uncommon
Serotonin syndrome (with concomitant use of serotonergic medicinal products, see sections 4.4 and 4.5) Not known Vascular disorders Hypotension Uncommon Respiratory, thoracic and mediastinal disorders Cough Uncommon Nasal congestion Uncommon Rhinorrhoea Uncommon Gastrointestinal disorders Faeces discoloured Very common Abdominal pain Common Vomitingc Common Nauseac Common Haematemesis Uncommon

System organ class
Adverse reaction
Frequency
Diarrhoea
Uncommon
Abdominal discomfort
Uncommon
Skin and subcutaneous tissue disorders
Skin discolouration (blue)b,c
Very common
Sweatingb
Very common
Ecchymosis
Uncommon
Night sweats
Uncommon
Pruritus
Uncommon
Rash
Uncommon
Telangiectasia
Uncommon
Photosensitivity
Not known
Musculoskeletal and connective tissue disorders
Pain in extremityb
Very common
Flank pain
Uncommon
Renal and urinary disorders
Chromaturia
Very common
Polyuria
Uncommon
Dysuria
Uncommon
General disorders and administration site conditions
Chest painb
Common
Pain
Uncommon
Chills
Uncommon
Injury, poisoning and procedural complications
Procedural nausea
Uncommon a The inclusion of anaphylactic reactions reported in the table is reflective of sporadic and spontaneous reporting in literature.
No event of anaphylactic reaction has been identified during clinical studies of Lumeblue.
b These terms are included as they were reported as very common or common in clinical studies with methylthioninium chloride via intravenous administration.
c See section below: Description of specific adverse reactions for more detail.

Description of specific adverse reactions

Frequent adverse reactions

In the pooled safety data from the clinical program, the most common related TEAE were chromaturia and discoloured faeces, as described above. In addition, skin discolouration has been reported in clinical studies with methylthioninium chloride administered via intravenous use, and this may interfere with in vivo monitoring devices (see section 4.4).

Serotonin syndrome

Serotonin syndrome has been reported with the use of methylthioninium chloride when administered via the intravenous use in combination with serotonergic medicinal products. Patients treated with methylthioninium chloride in combination with serotonergic medicinal products should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue treatment, and initiate supportive treatment (see section 4.5).

Nausea and vomiting

Nausea and vomiting are well recognised adverse reactions associated with the use of PEG-based bowel cleansing preparations, however in clinical studies, patients were more likely to experience nausea and vomiting when receiving Lumeblue in combination with a bowel preparation agent, than when receiving the bowel preparation alone.

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.

Serotonin syndrome

Serotonin syndrome has been reported with the use of methylthioninium chloride when administered intravenously in combination with serotonergic medicinal products. It is not known if there is a risk of serotonin syndrome when methylthioninium chloride is administered orally in preparation for colonoscopy. Patients treated with methylthioninium chloride in combination with serotonergic medicinal products should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, use of the medicinal product should be discontinued, and supportive treatment initiated (see section 4.5).

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.

Patients should be advised to take protective measures against exposure to light, because

photosensitivity may occur after administration of methylthioninium chloride.

General colouration

Methylthioninium chloride imparts a blue-green colour to urine, faeces and a blue colour to skin which may hinder a diagnosis of cyanosis.

Interference with in vivo monitoring devices

Inaccurate pulse oximeter readings

The presence of methylthioninium chloride in the blood may result in an underestimation of the oxygen saturation reading by pulse oximetry. If a measure of oxygen saturation is required after administration of the medicinal product, it is advisable to check oxygen saturation by CO-oximetry when available.

Bispectral index monitor

A fall in the bispectral index (BIS) has been reported following administration of methylthioninium chloride class products. If Lumeblue is administered during surgery, alternative methods for assessing the depth of anaesthesia should be employed.

Excipient warning

This medicinal product contains soya lecithin. If a patient is allergic to peanut or soya, this medicinal product must not be used (see section 4.3).

The following medicinal product interactions have been reported for medicinal products containing methylthioninium chloride.

Serotonergic medicinal products

Serious central nervous system (CNS) reactions have been recorded when methylthioninium chloride was administered via intravenous use to patients taking certain psychiatric medicinal products (see section 4.4). Reported cases occurred in patients taking specific serotonergic psychiatric medicinal products, namely a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), monoaminooxidase inhibitors or clomipramine. It is not known if there is a risk of serotonin syndrome when methylthioninium chloride is administered orally in preparation for colonoscopy.

In clinical studies maximal systemic exposure to methylthioninium chloride (maximum plasma concentration [Cmax]) was lower for orally administered methylthioninium chloride than for intravenous administered methylthioninium chloride, suggesting a lower risk of systemic effects such as serotonin syndrome occurring with oral methylthioninium chloride than for intravenous administered methylthioninium chloride.

Agents metabolised by cytochrome P450 enzymes

There is limited clinical information regarding the concomitant use of methylthioninium chloride with medicinal products that are metabolised by CYP isoenzymes. In vitro studies indicated that methylthioninium chloride inhibits a range of CYP isozymes in vitro, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. These interactions could have a clinical relevance with narrow therapeutic index medicinal products that are metabolised by one of these enzymes (e.g., warfarin, phenytoin, alfentanil, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus).

This medicinal product may be coadministered with anaesthetics / analgesics and/or sedative / anxiolytic medicinal products, often used during colonoscopy which are cleared through hepatic CYPs reactions such as: midazolam, propofol, diazepam, diphenhydramine, promethazine, meperidine, and fentanyl. The clinical consequences of changes in plasma concentrations of co-administered medicinal products which are substrates of these metabolic enzymes and transporters are not known but cannot be excluded.

Methylthioninium chloride induces CYP isozymes 1A2 and 2B6 in human hepatocytes culture, whereas it does not induce 3A4 at nominal concentrations up to 40 μM. However, these interactions are not expected to have any clinical relevance for the product single dose application.

Transporter interactions

There is limited clinical information regarding the concomitant use of methylthioninium chloride with medicinal products that are inhibitors of P-gp and OAT3. Based on in vitro studies, methylthioninium chloride was found to be a possible substrate of the membrane transport proteins P-gp, OCT2, MATE1 and MATE2-K and OAT3 and medicinal products which are inhibitors of these transporters have the potential to decrease excretion efficiency of methylthioninium chloride. Methylthioninium chloride is known to be 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 has the potential to transiently increase the exposure of medicinal products primarily cleared by renal transport involving the OCT2/MATE pathway, including cimetidine, metformin and acyclovir. However, the clinical impact of these in vitro interactions is expected to be minimal due to the short period of administration of the medicinal product (approximately 3 hours).

Pregnancy

There are no or limited amount of data from the use of methylthioninium chloride in pregnant women.
Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the evidence that methylthioninium chloride may pass the placenta, and the option to conduct a colonoscopy without supportive use of a visualisation agent, Lumeblue is contraindicated during pregnancy (see section 4.3). Women of childbearing potential must use effective contraception.

Breast-feeding

There is insufficient information on the excretion of methythioninium chloride / metabolites in human milk. Studies in animals have shown that there is the potential for excretion of methylthioninium chloride / metabolites during breast-feeding (see section 5.3). A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued prior to and after treatment with Lumeblue (see section 4.3).

Before administering the medicinal product to a woman who is breast feeding, consideration should be given as to whether the investigation could be reasonably delayed until the woman has ceased breast feeding or whether it is necessary to administer methylthioninium chloride as a visualisation agent for her colonoscopy, bearing in mind the theoretical secretion of active substance and/or metabolite in human milk. If administration is considered necessary, breast-feeding should be interrupted and the expressed feeds discarded. It is usual to advise that breast feeding can be restarted 8 days after the administration of methylthioninium chloride, based upon the methylthioninium chloride half life of 15 ± 5 hours.

Fertility

There is no information on the impact of methylthioninium chloride on human fertility. Animal and in

vitro studies with methylthioninium chloride have shown reproductive toxicity. In vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dose dependent manner. It has also been shown to inhibit the growth of cultured two-cell mouse embryos (see section 5.3).

Lumeblue has minor influence on the ability to drive and use machines.

Methylthioninium class medicinal products have been found to cause symptoms such as migraine, dizziness, balance disorder, somnolence, confusion and disturbances in vision. Patients who experience undesirable effects with a potential impact on the ability to drive or use machines safely, should refrain from these activities for as long as the undesirable effects persist.

Available information from other methylthioninium chloride class medicinal products administered via intravenous, or other non-oral uses in other indications, show that overdose can result in an exacerbation of adverse reactions. Administration of large intravenous doses (cumulative dose ≥ 7 mg/kg ) of a methylthioninium chloride caused nausea, vomiting, chest tightness, chest pain, dyspnoea, tachypnoea, tachycardia, apprehension, 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 effects lasted 2 to 12 hours following administration.

In case of overdose, the patient should be observed until signs and symptoms have resolved, including monitoring for cardiopulmonary, haematologic and neurologic toxicities, and instituting supportive measures as necessary.

Paediatric population

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 paediatric patient should be maintained under observation, the methaemoglobin level should be monitored and appropriate supportive measures taken as necessary.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Diagnostic agents, other diagnostic agents, ATC code: V04CX

Mechanism of action

Lumeblue is a delayed and extended-release multi-matrix (MMX) formulation in the form of tablets, each containing 25 mg of methylthioninium chloride as dried substance. The tablets are coated with an enteric coating that is stable at acidic pH (in the stomach) but breaks down at or above pH 7, normally achieved in the terminal ileum. Once the film coating has dissolved, the extended-release MMX formulation provides a slow release of the methylthioninium chloride dye, resulting in its homogeneous and prolonged dispersion on the surface of the colonic mucosa.

Methylthioninium chloride is known to be a “vital dye”, meaning “a dye or stain agent capable of penetrating living cells or tissues and not inducing immediate evident degenerative changes”.

Methylthioninium chloride is taken up across the cell membrane into the cytoplasm of actively absorbing cells such as those found in the small intestine and colon, thereby staining the epithelia of those organs. Vital, absorptive dyes such as methylthioninium chloride, enhance the superficial structure of lesions by exploiting the different degrees of active mucosal stain uptake, highlighting contrast and therefore differences between cell types.

Clinical efficacy and safety

A total of seven clinical studies have been conducted. The efficacy of this medicinal product was evaluated in one pivotal Phase 3 study (CB-17-01/06).

Study CB-17-01/06 was a Phase 3, multicentre, multinational, randomised, double-blind, placebo-

controlled, parallel-group study to evaluate the adenoma or carcinoma detection rate in patients undergoing safety or surveillance colonoscopy high definition white light (HDWL) colonoscopy after colonic mucosal staining and contrast enhancing with methylthioninium chloride tablets (compared to placebo tablets and gold standard HDWL colonoscopy alone). All subjects received 4 litres PEG- based bowel cleansing preparation starting in the late afternoon the day before the colonoscopy. The subjects were prescribed 3, 3, and 2 x 25 mg tablets after the second, third, and fourth litre of bowel preparation, respectively. The subjects drank at least 250 mL of preparation every 15 minutes, so that the intake of study medicinal product and bowel cleansing preparation was completed 4 hours after commencement of the bowel cleansing preparation. The study comprised both a full dose (200 mg) arm and a low dose (100 mg) arm, which was included to assist blinding of the full dose active arm.

Primary endpoint: adenoma detection rate (ADR)

The primary endpoint of Study CB-17-01/06 was the ADR defined as the proportion of subjects with at least one histologically proven adenoma or carcinoma. Histologically proven adenoma was defined as Vienna grade 3 to 4.2, or a traditional serrated adenoma (TSA) or sessile serrated adenoma (SSA).

Clinical studies show that methylthioninium chloride is well absorbed by the oral use, and rapidly taken up by the tissues. The majority of the dose is excreted in the urine, usually in the form of leucomethylthioninium chloride.

Absorption

Following the oral administration of methylthioninium chloride tablets at a total dose of 200 mg (8 prolonged-release tablets, 25 mg each) in healthy subjects, peak plasma concentration (Cmax) was 1.15 ± 0.26 mcg/mL, with a median time to peak concentration (Tmax) of 16 hours (10 – 24 hours).
Absolute bioavailability was calculated to be approximately 100%.

Biotransformation

Methylthioninium chloride inhibits a range of CYP isozymes in vitro, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5, and induces CYP isozymes 1A2 and 2B6, but not 3A4, in human hepatocytes culture. In vitro, methylthioninium chloride acts as a substrate and weak inhibitor of P-gp, and as a substrate of OAT-3, OCT2, MATE1 and MATE2-K (see sections 4.4 and 4.5).

Elimination

In a Phase 1 clinical study with 200 mg methylthioninium chloride cumulative excretion of unchanged methylthioninium chloride at 60 hours postdose was approximately 39 ± 16% of the administered dose. The mean terminal half-life (T1/2) was determined to be approximately 15 hours.

Special populations

In clinical studies, subgroup analyses based on age and gender did not indicate any difference in safety and efficacy. There are limited data in patients ≥ 75 years of age.

Elderly

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.

Posology

Adults

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.

Special populations

Elderly

No dose adjustment is necessary.

Renal impairment

In infants above 3 months, children and adolescents and in adults, the recommended dosage in patient with moderate renal impairment (eGFR 30-59 ml/min/1.73 m2) is 1-2 mg/kg per body weight. If a 1 mg/kg dose is given, a repeat dose of 1 mg/kg 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. The maximum recommended cumulative dose for the course of treatment is 2 mg/kg (see section 5.2).
In infants above 3 months, children and adolescents and in adults, the recommended dosage in patient with severe renal impairment (eGFR 15-29 ml/min/1.73 m2) is a single dose of 1 mg/kg per body weight.
The maximum recommended cumulative dose for the course of treatment is 1 mg/kg.
Methylthioninium chloride should be used with caution in infants 3 months old or younger and newborn infants with moderate to severe renal impairment (eGFR 15-59 ml/min/1.73 m2) since there is no data available and methylthioninium chloride is predominantly renally eliminated. Lower maximum cumulative doses (<0.5 mg/kg body weight) may be considered.
No dose adjustment is recommended in patients with mild renal impairment (eGFR 60-89 ml/min/1.73 m2).
The safety and efficacy of methylthioninium chloride in patients with end stage renal disease with and without dialysis has not yet been established. No data are available.

Hepatic impairment

No recommendation regarding dose adjustment can be given based on available study data.
See section 5.2.

Paediatric population

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.

Method of administration

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.

• Hypersensitivity to the active substance, or to any other thiazine dyes
• Patients with Glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of haemolytic anaemia
• Patients with nitrite-induced methaemoglobinaemia during treatment of cyanide poisoning
• Patients with methaemoglobinaemia due to chlorate poisoning
• Deficiency in NADPH (nicotinamide adenine dinucleotide phosphate) reductase.

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.

System organ class
Adverse reactions
Frequency
Blood and lymphatic system disorders
Methaemoglobinaemia,
Not known
Hyperbilirubinaemia1
Not known
Haemolytic anaemia
Not known
Immune system disorders
Anaphylactic reactions
Not known
Psychiatric disorders
Confusional state
Not known
Agitation
Not known
Nervous system disorders
Dizziness
Very common
Headache
Common
Anxiety
Common
Tremor
Not known
Fever
Not known
Aphasia
Not known
Paraesthesia
Very common
Dysgeusia
Very common
Serotonin Syndrome with concomitant use of serotonergic drugs (see section
4.4 and section 4.5).
Not known
Eye disorders
Mydriasis
Not known
Cardiac disorders
Cardiac arrhythmia
Not known
Tachycardia
Not known
Vascular disorders
Hypertension
Not known
Hypotension
Not known
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Not known
Tachypnoea
Not known
Hypoxia
Not known
Gastrointestinal disorders
Nausea
Very common
Vomiting
Common
Abdominal pain
Common
Faeces discoloration (blue-green)
Not known
Skin and subcutaneous tissue disorders
Skin discoloration (blue)
Very common
Sweating
Very common
Urticaria
Not known
Phototoxicity / Photosensitivity
Not known
Renal and urinary disorders
Chromaturia (blue-green)
Very common
General disorders and administration site conditions
Chest pain
Common
Local tissue necrosis at the injection site Not known
Injection site pain
Common
Investigations
Haemoglobin decreased
Not known
Musculoskeletal and connective tissue disorder
Pain in extremity
Very common
1 Reported in infants only

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.

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), monoamine oxidase inhibitors and opioids (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. Opioids, for example, tramadol, fentanyl, pethidine, and dextromethorphan, may also increase the risk of developing serotonin syndrome, when used in combination with methylthioninium chloride. 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 a potent reversible inhibitor of monoamine oxidase (see section 4.4).

Methylthioninium chloride is an in vitro inducer of CYP1A2. This interaction is not considered clinically relevant, since treatment with Methylthioninium chloride does not usually exceed one day.
In a drug interaction study, a single IV dose of 2 mg/kg Methylthioninium chloride Proveblue did not have a clinically relevant effect on the pharmacokinetics of midazolam (CYP3A4), caffeine (CYP1A2), omeprazole (CYP2C19), warfarin (CYP2C9), and dextromethorphan (CYP2D6).
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.

Individuals without methaemoglobinaemia

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.

Individuals with methaemoglobinaemia

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.

Paediatric population

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.

5.
PHARMACOLOGICAL PROPERTIES

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).

Paediatric population

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 mean (SD) terminal half-life of methylthioninium chloride after intravenous administration is 24.7 (7.2) h.
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.
Pharmocokinetics in renally impaired populations

After a single 1 mg/kg dose of methylthioninium chloride, AUC0-96h increased by 52%, 116%, and 192% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 ml/min/1.73 m2), moderate (eGFR 30-59 ml/min/1.73m2), and severe (eGFR 15-29 ml/min/1.73m2) renal impairment, respectively.
Cmax increased by 42%, 34%, and 15% in subjects with mild, moderate, and severe renal impairment respectively. The half-life was unchanged in patients with mild to moderate renal impairment. A longer mean half-life of 33 h were reported in subjects with severe renal impairment.

The AUC0-96h of Azure B after a single 1 mg/kg dose increased by 29%, 94%, and 339% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 ml/min/1.73 m2), moderate (eGFR 30- 59 ml/min/1.73m2), and severe (eGFR 15-29 ml/min/1.73m2) renal impairment, respectively. Cmax increased by 23%, 13%, and 65% in subjects with mild, moderate, and severe renal impairment respectively.

Pharmacokinetics in hepatically impaired populations