Leitlinien & Arzneimittelsicherheit

HOS-155165 · has-adverse-reaction-information · PDF-Seite 6

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. 6  System organ class Adverse reactions Frequency Blood and lymphatic system Methaemoglobinaemia, Not known disorders 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 Not known use of serotonergic drugs (see section 4.4 and section 4.5). Eye disorders Mydriasis

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HOS-155161 · has-contraindication-information · PDF-Seite 4

• 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.

HOS-155160 · has-indication-information · PDF-Seite 2

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).

HOS-155163 · has-interaction-information · PDF-Seite 5

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. 5

HOS-155164 · has-pregnancy-information · PDF-Seite 6

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.

HOS-155162 · has-warning-information · PDF-Seite 4

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 suppo

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