Indigo carmine 40 mg/5 mL, solution for injection

Solution for injection. pH: 3.0 to 5.9 Osmolarity: 0.05 osmol/L.

4.1 Therapeutic indications This medicinal product is for diagnostic use only. Indigo carmine is indicated for the intra-operative detection of suspected ureteral injuries during abdominal and pelvic surgery.4.2 Posology and method of administration **Posology** This medicinal product is to be injected by intravenous route. The recommended initial dosage is 1 ampoule of 5 mL by slow intravenous injection. A second ampoule may be injected 20 to 30 minutes after the first injection if necessary. *Paediatric population* The efficacy and safety of Indigo carmine in children has not been established (see section 4.4). *Patients with renal impairment* In patients with a clearance of creatinine ≥ 10 mL/min, Indigo carmine may be administered. In patients with a clearance of creatinine < 10 mL/min, Indigo carmine should not be used (see section 4.4). *Elderly* No dosage adjustment is necessary. *Patients with liver impairment* The excretion of Indigo carmine is mainly renal. There is no data in patients with liver impairment, however no dosage adjustment is necessary. **Method of administration** Slow intravenous injection under monitoring of arterial pressure and heart rate. *Precautions to be taken before administering the medicinal product* Considering the dark blue colour of Indigo carmine, a filtration is recommended during the intravenous administration (for example a filter of 0.45 µm, with a filtering surface of at least 2.8 cm2, composed of a hydrophilic polyethersulfone membrane).4.3 Contraindications Hypersensitivity to the active substance or to dyes.4.4 Special warnings and precautions for use **Special warnings** Indigotin (indigo carmine) may cause a transient elevation of blood pressure and reflex bradycardia especially in patients under general anaesthesia or under spinal anaesthesia. Rare idiosyncratic reactions with bradycardia and hypotension have also been reported. It is therefore necessary to monitor heart rate and blood pressure during and a few minutes after the injection. Intravenous injection should be stopped if the following symptoms occur: bradycardia, tachycardia, hypotension, hypertension, rash or erythema, respiratory symptoms such as dyspnea or bronchospasm. The efficacy and safety of Indigo carmine in children has not been established. In patients with a clearance of creatinine < 10 mL/min, the time to onset of indigotin (indigo carmine) in urines may be delayed for several minutes. Therefore, it should not be used in patients with clearance of creatinine < 10 mL/min. Indigotin (indigo carmine) may interfere with pulse or cerebral oximetric methods. A discolouration of urine may be observed following administration of indigotin (indigo carmine). **Precautions for use** Indigotin (indigo carmine) should be used with caution in case of: • high blood pressure, • low heart rate, • heart rate and conduction disorders, • concomitant use of medicines inducing bradycardia or affecting blood pressure or nitric oxide production, • coronary disorders due to its peripheral vasoconstrictor effect. The use of indigotin (indigo carmine) should be avoided in patients with: • hemodynamic instability, • uncontrolled heart failure, • history of allergic reactions.4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed.4.6 Fertility, pregnancy and lactation **Pregnancy** There are no or limited amount of data from the use of indigotin (indigo carmine) in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Indigo carmine is not recommended during pregnancy and in women of childbearing potential not using contraception. **Breast-feeding** It is unknown whether indigotin (indigo carmine) or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to abstain from indigotin (indigo carmine) administration taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. **Fertility** No fertility studies have been performed.4.7 Effects on ability to drive and use machines Not relevant.4.8 Undesirable effects The most common adverse reactions of indigotin (indigo carmine) are mainly related to its alpha-adrenergic activity and are of cardiovascular origin. Other idiosyncratic reactions such as changes in blood pressure or heart rate or anaphylactoid reactions have also been described. Serious adverse reactions of indigotin (indigo carmine) are very rare. Frequencies are defined as: 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) Frequency not known (cannot be estimated from the available data) **Cardiac disorders** *Very common:* • Hypertension (transient) • Bradycardia *Very rare:* • Tachycardia • Hypotension • Atrioventricular block **Respiratory, thoracic and mediastinal disorders** *Very rare*: • Dyspnea • Bronchial hyperreactivity **Skin and subcutaneous tissue disorders** *Very rare:* • Rash and erythema • Skin discolouration **Immune system disorders** *Very rare:* • Anaphylactoid reactions. **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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.4.9 Overdose No case of overdose has been reported in the literature for doses up to 80 mg of indigotin (indigo carmine) administered intravenously. **Symptoms** An overdose could induce a hypertensive crisis and severe bradycardia. **Management** In case of overdose, a peripheral vasodilator therapy may be considered.

5.1 Pharmacodynamic properties Pharmacotherapeutic class: DIAGNOSTIC AGENTS, ATC Code: V04CH02 Indigotin (indigo carmine) is a dye clinically used for diagnostic purposes. When it is intravenously administered, it causes dark blue discolouration of urine within 5-15 minutes of injection. This intense coloration enables the detection of any lesions of the urinary tract. No clinical study has been conducted. However, a meta-analysis of published studies was used to evaluate the diagnostic performance of indigotin (indigo carmine) in the detection of ureteral injury in abdominal and pelvic surgery. This meta-analysis showed that the sensitivity and specificity of the test with indigotin (indigo carmine) were high (respectively 96% and 100%) as well as the impact on the diagnosis process (positive predictive value of 86% and negative predictive value of 99.9% in a population with an incidence of ureteral lesions of 2.5%). Indigotin (indigo carmine) with its alpha-adrenergic properties triggers an increase of peripheral vascular resistance, resulting in moderate and transient increase of blood pressure and a probably reactional moderate decrease of heart rate.5.2 Pharmacokinetic properties Pharmacokinetic data are rare. Indigotin (indigo carmine) has a plasma half-life of 4.5 minutes. Indigo carmine is largely bound to protein plasma. It is quickly eliminated from the plasma compartment and it is easily and largely eliminated by the kidney. A small amount is excreted in the bile. In case of renal function impairment, the average time of excretion can be extended for several minutes.5.3 Preclinical safety data Acute toxicity data for indigotin (indigo carmine) are available from rat and mouse studies. In rats, the LD50 (median lethal single dose) is 93 mg/kg by intravenous route while in mice the LD50 is 405 mg/kg by subcutaneous route. No carcinogenicity study has been conducted by intravenous route with indigotin (indigo carmine). However, long-term studies in rats (oral) and mice (subcutaneous) have not revealed any carcinogenic effects. In oral dosing studies performed in rats and rabbits, doses of indigotin (indigo carmine) up to 250 mg/kg/day did not produce any teratogenic effects. However oral bioavailability of indigotin is approximately 3%.

6.1 List of excipients Water for injections.6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.6.3 Shelf life 2 years. After opening: this product should be used immediately.6.4 Special precautions for storage This product does not require any special storage conditions. For storage conditions after first opening of the medicinal product, see section 6.3.6.5 Nature and contents of container 5 mL ampoules in type I brown glass. Box of 10 ampoules.6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.