LUMEBLUE Prolonged-release tablet Ref.[50405] Active ingredients: Methylthioninium chloride

Serotonin syndrome

Serotonin syndrome has been reported with the use of methylthioninium chloride when administered via the intravenous route 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, discontinue use of Lumeblue, and initiate supportive treatment (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.

Advise patients 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 Lumeblue, 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

Lumeblue 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 route 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 [C_max]) 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).

Lumeblue 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 Lumeblue single dose application.

Transporter interactions

There is limited clinical information regarding the concomitant use of Lumeblue 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 Lumeblue 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 Lumeblue (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 Lumeblue 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.

Summary of safety profile

Lumeblue commonly causes chromaturia (32.4%) and discoloured faeces (13.4%), which gradually diminish over the following days. Lumeblue 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 <1/1000), 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.

^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 route, 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 route 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.

Not applicable.