Methylthioninium chloride Cosmo

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Methylthioninium chloride Cosmo 25 mg prolonged-release tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each prolonged-release tablet contains 25 mg of methylthioninium chloride. 
 
Excipients with known effect 
 
Methylthioninium chloride Cosmo contains 3 mg soya lecithin per prolonged-release tablet.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Prolonged-release tablet. 
Off white to light blue, round, biconvex, enteric coated tablets, with approximate dimensions of 
9.5 mm x 5.3 mm. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Methylthioninium chloride Cosmo is indicated as a diagnostic agent enhancing visualisation of 
colorectal lesions in adult patients undergoing screening or surveillance colonoscopy (see section 5.1). 
 
4.2 Posology and method of administration 
 
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 the 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 population 
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).  
 



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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  
 
Methylthioninium chloride Cosmo is 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 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. 
 
4.3 Contraindications 
 

• 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). 

 
4.4 Special warnings and precautions for use 
 
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 Methylthioninium chloride Cosmo, 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. 
 



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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 Methylthioninium chloride Cosmo, 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 Methylthioninium chloride Cosmo is administered during surgery, 
alternative methods for assessing the depth of anaesthesia should be employed. 
 
Excipient warning  
 
Methylthioninium chloride Cosmo contains soya lecithin. If a patient is allergic to peanut or soya, this 
medicinal product  must not be used (see section 4.3). 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 [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).  
 
Methylthioninium chloride Cosmo 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, 



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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 Methylthioninium chloride Cosmo single dose 
application. 
 
Transporter interactions 
 
There is limited clinical information regarding the concomitant use of Methylthioninium chloride 
Cosmo 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 Cosmo 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 Methylthioninium chloride Cosmo 
(approximately 3 hours). 
 
4.6 Fertility, pregnancy and lactation 
 
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, 
Methylthioninium chloride Cosmo 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 Methylthioninium 
chloride Cosmo (see section 4.3).  
 
Before administering Methylthioninium chloride Cosmo 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 



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manner. It has also been shown to inhibit the growth of cultured two-cell mouse embryos (see 
section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Methylthioninium chloride Cosmo 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. 
 
4.8 Undesirable effects 
 
Summary of safety profile 
 
Methylthioninium chloride Cosmo commonly causes chromaturia (32.4%) and discoloured faeces 
(13.4%), which gradually diminish over the following days. Methylthioninium chloride Cosmo 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 Methylthioninium chloride 
Cosmo. 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. 
 



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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 
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 Methylthioninium chloride COSMO. 
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).  



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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 Methylthioninium chloride Cosmo 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. 
 
4.9 Overdose 
 
Available information from other methylthioninium chloride class medicinal products administered 
via intravenous, or other non-oral routes 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 of Methylthioninium chloride Cosmo, 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 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Diagnostic agents, other diagnostic agents, ATC code: V04CX  
 
Mechanism of action 
 
Methylthioninium chloride Cosmo 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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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 of Methylthioninium chloride Cosmo 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 COSMO 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 2x 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). 
Histologically proven carcinoma was defined as Vienna grade 4.3 to 5.b. The primary analysis 
population was defined as all randomised subjects who received at least one dose of study treatment 
and underwent colonoscopy, regardless of the completion status. The primary endpoint was analysed 
through a logistic regression with treatment, centre, age, gender, reason for colonoscopy, and number 
of excisions included in the regression model as fixed effects. 
Primary endpoint results are provided in table 1 below. 
 

Table 1: Efficacy results from study CB-17-01/06 - primary endpoint: ADR  

Adenoma detection rate (ADR) Methylthioninium chloride Cosmo vs. placebo 
Absolute value 56.29% vs. 47.81% 
Magnitude of effect 8.48% 

Adjusted odds ratio (OR) Point estimate 
95% 

Confidence 
interval limits 

p-value 

OR without logistic regression  1.41 [1.09, 1.81] 0.0099 
OR with logistic regression 1.46 [1.09, 1.96] 0.0106 
OR with logistic regression excluding 
excisions as regression covariate 1.51 [1.15, 1.97] 0.0027 

 



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Secondary endpoint: false positive rate (FPR) 
 
The FPR was introduced to control for possible false positive study results, in that a high FPR would 
indicate a higher sampling rate in the Methylthioninium chloride Cosmo group without a concomitant 
increase in ‘hit rate’ for detecting patients with positive lesions (adenomas or carcinomas). In this 
occurrence, a positive difference between Methylthioninium chloride Cosmo and placebo (i.e., 
increase in the FPR) was hypothesised and a maximum threshold (non-inferiority margin) was set at 
15%. 
Table 2 and table 3 below present the FPR at both a subject and excision level. Methylthioninium 
chloride Cosmo was statistically not inferior to placebo in FPR at both the subject and excision level. 
FPR at the subject level was numerically lower (-6.44%) in the treatment group than in the placebo 
group. At the excision level, the FPR of Methylthioninium chloride Cosmo was numerically slightly 
greater (+2.63%) than placebo, however this was not considered clinically significant. These data 
demonstrate the effectiveness of Methylthioninium chloride Cosmo at visualising lesions that were 
subsequently determined to be adenoma and carcinoma. 
 

Table 2: Efficacy results from the study CB-17-01/06 - secondary endpoint: FPR (subject level) 

False positive rate (FPR) (subject level) Methylthioninium chloride Cosmo / placebo 
Absolute value 23.31% vs. 29.75% 
Adjusted odds ratio (OR) 

Point estimate 
95% 

Confidence 
interval limits 

p-value 

Magnitude of effect = difference in FPR (≥15% 
threshold for rejecting null hypothesis)  -6.44 [-13.07, 0.19] <0.0001 

 

Table 3: Efficacy results from the study CB-17-01/06 - secondary endpoint: FPR (excision level) 

False positive rate (FPR) (excision level) Methylthioninium chloride Cosmo / placebo 
Absolute value 49.79% vs. 47.16% 
Adjusted odds ratio (OR) 

Point estimate 
95% 

Confidence 
interval limits 

p-value 

Magnitude of effect = difference in FPR (≥15% 
threshold for rejecting null hypothesis)  2.63 [-1.55, 6.81] <0.0001 

 
The tables below present further prespecified and post-hoc clinically meaningful endpoints from the 
pivotal Phase III study (CB17-01/06): 
 

Table 4: Efficacy results from the study CB-17-01/06 - secondary endpoint: proportion of 
subjects with at least one adenoma 

Proportion of subjects with at least one 
adenoma 

Methylthioninium chloride Cosmo / placebo 

Absolute value 55.88% vs. 47.18% 
Adjusted odds ratio (OR) 

Point estimate 
95% 

Confidence 
interval limits 

p-value 

Magnitude of effect = difference in proportion  8.69 [2.41, 14.98] 0.0082 
OR without logistic regression  1.42 [1.10, 1.83] 0.0082 

 



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Table 5: Efficacy results from the study CB-17-01/06 - exploratory endpoint: proportion of 
subjects with at least one non-polypoid lesion 

 

Table 6: Post hoc analysis: proportion of subjects with at least one non-polypoid adenoma or 
carcinoma 

 
  
5.2 Pharmacokinetic properties 
 
Clinical studies show that methylthioninium chloride is well absorbed by the oral route, 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 Cosmo 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 μg/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 Cosmo 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. 

Proportion of subjects with at least one non-
polypoid lesion 

Methylthioninium chloride Cosmo / placebo 

Absolute value 43.92% vs. 35.07% 
Adjusted odds ratio (OR) 

Point estimate 
95% 

Confidence 
interval limits 

p-value 

Magnitude of effect = difference in proportion  8.84% [2.70, 14.99] 0.0056 
OR without logistic regression  1.45 [1.12, 1.88] 0.0056 
OR with logistic regression 1.66 [1.21, 2.26] 0.0015 

Proportion of subjects with at least one non-
polypoid adenoma or carcinoma 

Methylthioninium chloride Cosmo / placebo 

Absolute value 25.77% vs. 19.21% 
Adjusted odds ratio (OR) 

Point estimate 
95% 

Confidence 
interval limits 

p-value 

Magnitude of effect = difference in proportion 6.57% [1.31, 11.82] 0.0167 
OR without logistic regression 1.46 [1.08, 1.98] 0.0167 



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Elderly 
Methylthioninium chloride Cosmo was investigated in subjects undergoing screening or surveillance 
colonoscopy, with a mean age of 58.4 years (range 21 to 80 years) and 250 subjects at least 65 years of 
age, thus the subject population was representative of the intended clinical population, however there 
is limited data in patients ≥75 years of age. Overall, the safety profile of this medicinal product was 
broadly similar regardless of age. It is therefore proposed that neither warnings nor dose adjustments 
are required in respect of age. 
 
Renal impairment 
Retrospective analysis of the safety dataset identifying subjects with some degree of renal impairment 
concluded that the incidence and pattern of TEAE in subjects receiving Methylthioninium chloride 
Cosmo was consistent with the observed pooled safety database, and thus no warnings nor dose 
adjustments are required in respect to mild renal impairment. There are no data in patients with 
moderate to severe renal impairment, and therefore the medicinal product should be used with caution 
in patients with moderate to severe renal impairment (see section 4.2).  
 
Hepatic impairment 
Retrospective analysis of the safety dataset identifying subjects with some degree of hepatic 
impairment concluded that the incidence and pattern of TEAE in subjects receiving Methylthioninium 
chloride Cosmo was consistent with the observed pooled safety database, and thus no warnings nor 
dose adjustments are required in respect to mild to moderate hepatic impairment. There are no data in 
patients with severe hepatic impairment. 
 
5.3 Preclinical safety data 
 
Repeated dose toxicity 
 
In repeat dose toxicity studies, with Methylthioninium chloride Cosmo, no observed adverse effect 
level (NOAEL) was considered to be 600 mg/four days. Therefore, effects in non-clinical studies were 
observed only at exposures considered sufficiently in excess of the maximum human exposure 
indicating little relevance to clinical use. 
 
Genotoxicity 
 
Methylthioninium chloride has been shown to be mutagenic in gene mutation assays in bacteria and 
mouse lymphoma cells, but not in vivo mouse micronucleus assay when administered intravenously at 
62 mg/kg.  
 
Carcinogenicity 
 
Some evidence of carcinogenic activity of methylthioninium chloride in male mice and rats, equivocal 
evidence of carcinogenic activity in female mice and no evidence of carcinogenic activity in female 
rats. 
 
Reproductive toxicology 
 
In animal studies, methylthioninium chloride produced adverse developmental outcomes in rats and 
rabbits when administered orally during organogenesis. As a precautionary measure, the use of 
methylthioninium chloride during pregnancy is contraindicated (see section 4.3). 
 
Studies reported in literature suggest that exposure to methylthioninium chloride results in the 
reduction of sperm motility in vitro and teratogenic effects on embryo-foetal developmental effects in 
rats and rabbits. However, there were no consistent effects of methylthioninium chloride 
administration on reproductive system measures in male or female rats after 3-months oral treatment. 
 
 



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6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Stearic acid 50 (E570) 
Soya lecithin (E322) 
Microcrystalline cellulose (E460) 
Hypromellose 2208 (E464) 
Mannitol (E421) 
Talc (E553b) 
Silica colloidal anhydrous (E551) 
Magnesium stearate (E470b) 
 
Tablet coating 
 
Methacrylic acid - methyl methacrylate copolymer (1:1) 
Methacrylic acid - methyl methacrylate copolymer (1:2) 
Talc (E553b) 
Titanium dioxide (E171) 
Triethyl citrate (E1505) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Polyamide/aluminium/PVC foil blister with aluminium push-through foil. 
Packs contain 8 prolonged-release tablets. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
 



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7. MARKETING AUTHORISATION HOLDER 
 
Cosmo Technologies Ltd 
Riverside II 
Sir John Rogerson’s Quay 
Dublin 2 
Ireland 
+353 1817 0370  
info@cosmotechnologies.com 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1470/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 
  

http://www.ema.europa.eu/


15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



16 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Cosmo S.p.A 
Via C. Colombo, 1 
20020, Lainate 
Milan,  
Italy 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription. 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
  



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



19 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Methylthioninium chloride COSMO 25 mg prolonged-release tablets  
methylthioninium chloride  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each prolonged-release tablet contains 25 mg methylthioninium chloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains soya lecithin. Read the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Prolonged-release tablets 
8 prolonged-release tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use.  
Swallow whole. Do not crush or chew the tablets.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



20 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Cosmo Technologies Ltd 
Riverside II 
Sir John Rogerson’s Quay 
Dublin 2 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1470/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Methylthioninium chloride COSMO 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
  



21 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Methylthioninium chloride COSMO 25 mg prolonged-release tablets 
methylthioninium chloride 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Cosmo Technologies Ltd. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



23 

 
Package leaflet: Information for the patient  

 
Methylthioninium chloride COSMO 25 mg prolonged-release tablets 

methylthioninium chloride 
 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them. 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 
 
What is in this leaflet 
 
1. What Methylthioninium chloride COSMO is and what it is used for  
2. What you need to know before you take Methylthioninium chloride COSMO  
3. How to take Methylthioninium chloride COSMO 
4. Possible side effects  
5. How to store Methylthioninium chloride COSMO 
6. Contents of the pack and other information 
 
 
1. What Methylthioninium chloride COSMO is and what it is used for 
 
Methylthioninium chloride COSMO contains methylthioninium chloride (also known as methylene 
blue). This medicine is a blue dye.  
 
This medicineis used in adults to temporarily stain the colon (large bowel) before colonoscopy, in 
which a flexible instrument is inserted into the rectum to view inside the bowel. The staining allows 
the doctor to see the lining of the colon more clearly and improves the detection of abnormalities.  
 
 
2. What you need to know before you take Methylthioninium chloride COSMO 
 
Do not take Methylthioninium chloride COSMO 
• if you are allergic to methylthioninium chloride, peanut or soya, or any of the other 

ingredients of this medicine (listed in section 6);  
• if you have been told you have glucose-6-phosphate dehydrogenase (G6PD) deficiency; 
• if you are pregnant or think you may be pregnant, or are breastfeeding as your doctor may 

decide that you do not need to take this medicine before your procedure.  
 
Warnings and precautions  
Talk to your doctor or pharmacist before taking this medicine: 
• If you are taking certain antidepressant medicine or a medicine for psychiatric illness. Such as: 

- selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine, 
fluvoxamine, paroxetine, sertraline, citalopram, escitalopram and zimeldine; 

- bupropion, venlafaxine, mirtazapine, clomipramine, buspirone; 
- medicines classified as monamine oxidase inhibitors (often used for treating depression). 

Giving methylthioninium chloride injection (into a vein) in patients also taking these medicines 
has sometimes resulted in a life-threatening complication called serotonin syndrome. It is not 
known if serotonin syndrome can occur when methylthioninium chloride is given as a tablet. 
Your doctor will decide what to do if you are taking an antidepressant or another medicine for a 
psychiatric illness.  



24 

 
Children and adolescents 
Methylthioninium chloride COSMO should not be given to children and adolescents under 18 years of 
age as it is not known if the medicine is safe and effective in this age group. 
 
Other medicines and Methylthioninium chloride COSMO 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
 
Other medicines and Methylthioninium chloride COSMO taken together may affect how they each 
work or are processed and removed from the body. 
 
In addition to antidepressants and the other medicines for psychiatric illness mentioned under 
‘Warnings and Precautions’, you should tell your doctor before you take this medicine if you are also 
taking or have recently been given: 
• Medicines to treat irregular heart beats such as amiodarone, digoxin and quinidine 
• Warfarin, to prevent blood clots  
• Medicines to treat cancer such as alectinib, everolimus, lapatinib, nilotinib and topotecan  
• Medicines to prevent organ transplant rejection such as ciclosporin, sirolimus and tacrolimus 
• Medicines to treat HIV infection such as ritonavir and saquinavir 
• Medicines to treat migraine such as dihydroergotamine, ergotamine 
• Medicines used to treat anxiety or insomnia, such as diazepam 
• Sedative medicines such as midazolam and propofol  
• Antihistamine medicines to treat allergies such as diphenhydramine or promethazine 
• Probenecid to treat gout 
• Phenytoin to treat epilepsy 
• Pimozide to treat psychosis or schizophrenia 
• Medicines to treat severe pain such as alfentanil, fentanyl and pethidine (also known as 

meperidine) 
• Cimetidine to treat stomach ulcers and acid reflux 
• Metformin to treat type 2 diabetes  
• Aciclovir to treat herpes simplex virus infections (e.g. cold sores, genital warts) and varicella–

zoster virus infections (e.g. chicken pox, shingles) 
 
Pregnancy and breast-feeding  
If you are pregnant, think you may be pregnant or are planning to have a baby, do not use 
Methylthioninium chloride COSMO as it is not known whether this medicine can harm your unborn 
baby. 
If you are breast-feeding, ask your doctor or pharmacist for advice before taking this medicine.  
Your doctor may decide that you do not need to take this medicine if you require a colonoscopy whilst 
breast-feeding. 
 
Driving and using machines 
It is unlikely that taking Methylthioninium chloride COSMO will affect your ability to drive or use 
machines. However if you experience any side effects that could impair your ability to drive or use 
machines safely, such as migraine, feeling dizzy, or disturbance to your vision, then you should not 
drive or use machines until you feel better. 
 
Methylthioninium chloride COSMO contains soya lecithin 
If you are allergic to peanut or soya, do not take this medicine. 
 
 
3. How to take Methylthioninium chloride COSMO 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 



25 

The medicine is supplied as tablets. These must be swallowed whole because they have a special 
coating to make sure that they pass through your stomach and only break up in your intestines to 
release the methylthioninium chloride that stains the colon blue. You must not crush or chew them. 
 
You will be given a pack containing 8 tablets (a total of 200 mg methylthioninium chloride). These 
must all be taken over a period of 2 hours, the night before your colonoscopy. Your doctor will explain 
how you should take the tablets, which are normally taken together with a bowel cleansing preparation 
(a medicine to clear out your colon).  
 
Take the tablets as instructed by your doctor.  
 
Typical instructions are: 
 
1. After drinking at least 1 litre of the bowel cleansing preparation (or water) take the first dose of 

3 tablets. 
 

2. Wait 1 hour then take the second dose of 3 tablets.  
 

3. Wait another hour, then take the final dose of 2 tablets. 
 
If you take more Methylthioninium chloride COSMO than you should 
The box contains one complete dose of Methylthioninium chloride COSMO. Therefore you cannot 
take more Methylthioninium chloride COSMO than you should. However, if you take more tablets 
than you should, you might get some of the side effects listed in section 4. If you think you have taken 
more of this medicine than you should, tell your doctor or nurse as soon as possible.  
If you notice any of the following symptoms you should tell your doctor straight away: 
• Feeling or being sick, or stomach pain 
• Abnormally fast beating of the heart, or chest pain 
• Tight chest or difficulty breathing (e.g. breathlessness) 
• Confusion, dizziness, or headache 
• Sweating, tremor, feeling weak, paler skin than usual, or skin turning blue 
•  An increase in methaemoglobin (an abnormal form of haemoglobin in the blood); 
•  High blood pressure. 
 
If you forget to take one or more of the doses of Methylthioninium chloride COSMO 
Do not take a double dose to make up for a forgotten tablets, take the next dose of tablets according to 
the bowel cleansing schedule given to you by your doctor, it may be helpful to set an alarm to remind 
you when to take the medicine.  
 
If you stop taking Methylthioninium chloride COSMO 
At your colonoscopy, tell your doctor that you did not take all the tablets.  
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The following side effects are common, but tell your doctor or nurse if you are worried about any side 
effect you get: 
 
Very common (may affect more than 1 in 10 people) 
• Discoloured urine 
• Discoloured faeces 
• Dizziness 
• Changes in your sense of taste 
• Pins and needles sensation, tingling or prickling 



26 

• Pain or discomfort in your hands or feet 
• Blue discolouration of the skin 
• Sweating 
 
Common (may affect up to 1 in 10 people) 
• Nausea 
• Vomiting 
• Stomach or chest pain 
• Headache 
• Anxiety 
 
Uncommon (may affect up to 1 in 100 people) 
• Cold-like symptoms, including blocked or runny nose 
• Migraine 
• Low blood pressure 
• Cough 
• Vomiting blood 
• Bruising-like discolouration of the skin,  
• Night sweats 
• Itchy skin 
• Rash 
• Spidery veins 
• Pain in the back or sides 
• Abnormally large amounts of urine, or pain or difficulty when passing urine 
• General pain 
• Chills 
• Signs of serotonin syndrome, such as muscle spasms, clumsiness, tremors, confusion or other 

mental changes 
• Signs of an anaphylactic reaction, such as itchy rash, throat or tongue swelling, shortness of breath. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Methylthioninium chloride COSMO 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not use this medicine if the pack is damaged or shows signs of tampering. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 



27 

6. Contents of the pack and other information 
 
What Methylthioninium chloride COSMO contains  
The active substance is methylthioninium chloride. Each prolonged-release tablet contains 25 mg 
methylthioninium chloride. 
- The other ingredients are: 
* Tablet core: stearic acid 50 (E570), soya lecithin (E322) – see section 2 under ‘Methylthioninium 

chloride COSMO contains soya lecithin’, microcrystalline cellulose (E460), 
hypromellose 2208 (E464), mannitol (E421), talc (E553b), silica colloidal anhydrous (E551), 
magnesium stearate (E470b) 

* Film coating: methacrylic acid–methyl methacrylate copolymer, talc (E553b), titanium 
dioxide (E171), triethyl citrate (E1505) 

 
What Methylthioninium chloride COSMO looks like and contents of the pack 
Methylthioninium chloride COSMO prolonged-release tablets are off-white to light blue, round, 
biconvex, enteric-coated tablets. The prolonged-release tablets are provided in blister packs containing 
8 tablets.  
 
Marketing Authorisation Holder 
Cosmo Technologies Ltd 
Riverside II 
Sir John Rogerson’s Quay 
Dublin 2 
Ireland 
+353 1817 0370  
info@cosmotechnologies.com 
 
Manufacturer 
Cosmo S.p.A 
Via C. Colombo, 1 
20020, Lainate 
Milan,  
Italy 
 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET