Lumeblue (previously Methylthioninium chloride Cosmo) · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-216554 · has-adverse-reaction-information · PDF-Seite 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 Not known concomitant use of serotonergic medicinal products, see sections 4.4 and 4.5) Vascular disorders Hypotension Uncommon Respiratory, thoracic and Cough Uncommon mediastinal disorders Nasal congestion Uncommon Rhinorrhoea Uncommon Gastrointestinal disorders Faeces discoloured Very common Abdominal pain Common

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HOS-216550 · has-contraindication-information · PDF-Seite 3

• 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).

HOS-216549 · has-indication-information · PDF-Seite 2

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

HOS-216552 · has-interaction-information · PDF-Seite 4

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). 4 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

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HOS-216553 · has-pregnancy-information · PDF-Seite 5

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 5 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).

HOS-216551 · has-warning-information · PDF-Seite 3

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 3 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).