SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Indigo carmine 40 mg/5 mL solution for injection

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Indigotin (indigo carmine)............................................................40 mg

For 5 mL of solution for injection.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

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

4    CLINICAL PARTICULARS

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 impairement

In patients with a clearance of creatinine may be administered.

In patients with a clearance of creatinine used (see section 4.4).

Elderly

No dosage adjustment is necessary.

Patients with liver impairement

The excretion of Indigo carmine is mainly renal. There is no data in patients with liver impairement, 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 pm, 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 oxymetric 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:

•    concomitant use of medicines inducing bradycardia,

•    heart rate and conduction disorders,

•    high blood pressure,

•    low heart rate,

•    coronary disorders due to its peripheral vasoconstrictor effect.

The use of indigotin (indigo carmine) should be avoided in patients with:

•    uncontrolled heart failure,

•    history of allergic reactions,

•    hemodynamic instability.

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.

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.

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 availability 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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION    HOLDER

SERB S.A.

Avenue Louise 480 1050 Brussels Belgium

8    MARKETING AUTHORISATION    NUMBER(S)

PL 43956/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/06/2015

10    DATE OF REVISION OF THE TEXT

05/06/2015