4.1. Therapeutic indications

This medicinal product is for diagnostic use only. It is indicated in:

• Oncology:

Intraoperative identification of the sentinel lymph node and visualisation of the lymphatic pathways in cases of breast cancer.

• Ophthalmic angiography diagnostics:

Measurement of perfusion of the choroid.

• Liver function diagnostics:

- Measurement of liver blood flow

- Measurement of excretory function of the liver.

• Cardiac, circulatory and micro-circulatory diagnostics:

- Measurement of cardiac output and stroke volume

- Measurement of circulating blood volumes

- Measurement of cerebral perfusion

4.2. Posology and method of administration

Single dose per measurement in adults, elderly, adolescents, children:

Intraoperative sentinel node location and visualisation of lymph ducts (oncology):

The dose varies from 5 to 10 mg (i.e. 2 to 4 mL of a 2.5 mg/mL solution).

Ophthalmic angiography :

0.1 to 0.3 mg/kg body weight as intravenous bolus injection

Liver function diagnostics:

0.25 to 0.5 mg/kg body weight as intravenous bolus injection

Cardiac, circulatory, micro-circulatory and tissue perfusion diagnostics as well as cerebral blood flow:

0.1 to 0.3 mg/kg body weight as intravenous bolus injection

The total dose injected should not exceed 0.5 mg/kg.

Method of administration

In oncology:

Subcutaneous route.

The injection is given intraoperatively via the subcutaneous route in the periareolar or peritumoral zone.

The injection is given approximately 10 minutes before the start of surgery. The breast is massaged for a few minutes after the injection.

Measurement of cardiac, circulatory and cerebral blood flow as well as liver function diagnostics and ophthalmologic angiography:

For cardiac, circulatory, microcirculatory and liver function diagnostics, as well as for ophthalmologic angiography, Zyogreen is intended for intravenous injection via an injection needle, a central or peripheral catheter or cardiac catheter.

The administration and site of Zyogreen are of critical importance for the quality of the measurements. In principle, for obtaining optimal quality first pass indicator dilution curves, the injection should be as close as possible to the vascular bed, organ or tissue of interest.

On peripheral intravenous injection, venipuncture should be done after application of a tourniquet. After release of the tourniquet, Zyogreen should be injected immediately and the arm should be raised. This ensures rapid transport of the dye from the site of injection and peripheral injection is then practically equivalent to central venous injection.

Areas under the first pass curve, transit time, half-life, plasma disappearance rate and retention rate of Zyogreen can be determined:

a. non-invasively by pulse dye densitometry or near infrared spectroscopy

b. invasively by fibre optic probes/catheters in suitable vessels

c. conventionally by determination of the concentration either by continuous withdrawal of heparinised blood through a cuvette densitometer or by collection of blood samples and measurement of the plasma concentration in a photometer

Evaluation of fundus perfusion in ophthalmic angiography

The perfusion of the fundus of the eye can be determined and quantified by ophthalmic fluorescence angiography.

Measurement of tissue perfusion

Tissue perfusion of the superficial tissue layers can be made visible and quantified by near infrared fluorescence video angiography.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Other contraindications include:

• patients with hyperthyroidism, patients with autonomic thyroid adenomas.

• in-vitro experiments have shown that indocyanine green displaces bilirubin from its protein binding. Zyogreen should not be used in premature infants or neonates in whom an exchange transfusion is indicated due to hyperbilirubinemia,

• if injection of Zyogreen was poorly tolerated in the past it must not be used again, since severe anaphylactic reactions might occur.

• patients with hypersensitivity to iodine.

4.4. Special warnings and precautions for use

• There is a risk of hypersensitivity reactions with Zyogreen irrespective of the route of administration and the dose administered.

• Serious allergic reactions (such as Quincke's oedema or anaphylactic reaction) have been reported very rarely after administration of indocyanine green alone or after concomitant administration of indocyanine green and fluorescein. This risk means that the patient must be monitored during and after the injection of these products. Zyogreen should only be administered under the supervision of a physician, and emergency resuscitation facilities should be available for immediate use. Patients should be monitored for at least an hour after administration of indocyanine green for the occurrence of hypersensitivity reactions.

• The iodine content of Zyogreen can interfere with thyroid tests performed before or after administration of the dye. Therefore, radio-active iodine uptake studies should not be performed for at least a week following the use of Zyogreen.

• When Zyogreen is administered intradermally or subcutaneously, patients should be advised to avoid direct sun or UV radiation for at least 1 week, or until any greenish discoloration at the injection site has disappeared.

• Heparin preparations containing sodium bisulphite may reduce the absorption peak of indocyanine green in plasma and blood. Therefore heparin should not be used as an anticoagulant for the collection of samples for analysis.

4.5. Interaction with other medicinal products and other forms of interaction

The clearance of indocyanine green may be altered by medicinal products that interfere with liver function.

The absorption peak of indocyanine green is reduced by injectables containing sodium bisulphite (particularly in combination with heparin).

4.6. Fertility, pregnancy and lactation

Pregnancy

Data on a limited number (242) of exposed pregnancies indicate no adverse effects of indocyanine green on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. No studies for reproduction, teratogenicity, or carcinogenic properties in animals are available. The potential risk for humans is unknown. Caution should be exercised when prescribing to pregnant women. Repeated applications on one day have to be avoided.

Lactation

It is not known whether this medicinal product is excreted in human milk. Because many medicinal products are excreted in human milk, caution should be exercised when indocyanine green is administered to a nursing woman.

Fertility

There are no data regarding the effect of indocyanine green on fertility.

4.7. Effects on ability to drive and use machines

Zyogreen has minor influence on the ability to drive and use machines. Impaired vision has been reported with Zyogreen when used in ophthalmology.

4.8. Undesirable effects

Immediate hypersensitivity reactions may occur. These reactions may include one or more of the following effects, occurring concomitantly or successively: cutaneous (urticaria, pruritus, facial oedema), respiratory (bronchospasm, laryngospasm, shortness of breath), gastrointestinal (nausea) and/or cardiovascular reactions (acceleration of heart rate, fall in blood pressure, cardiac arrest). Any of these effects may be a warning sign of an anaphylactic reaction.

Adverse reactions are listed in the following table by system organ class and frequency, according to the following categories: Very common (≥ 1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000, <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

System organ class

Undesirable effects

Frequency of undesirable effects

Immune system disorders

Anaphylactic reaction*

Very rare

Hypersensitivity

Not known

Vascular disorders

Hot flushes

Rare

Gastrointestinal disorders

Vomiting

Uncommon

Nausea

Uncommon

Skin and subcutaneous tissue disorders

Rash

Rare

Urticaria

Rare

Skin reaction

Rare

Pruritus

Rare

Hyperhidrosis

Rare

Angioedema

Very rare

Alteration of skin colour**

Not known

General disorders and abnormalities at the administration site

Dizziness

Rare

Staining at the injection site

Not known

*Anaphylactic reaction after administration of indocyanine green alone or after concomitant administration of indocyanine green and fluorescein.

**Temporary discolouration of the integuments observed in the event of accidental para-venous injection.

If, contrary to expectations, symptoms of anaphylaxis do occur, the following immediate measures should be taken:

- stop further administration of Zyogreen, leave injection catheter or cannula in the vein

- keep airways free

- inject 100-300 mg hydrocortisone or a similar preparation by rapid intravenous injection

- substitute volume with isotonic electrolyte solution

- give oxygen, monitor circulation

- slowly administer antihistamines intravenously

The following additional measures are indicated in cases of anaphylactic shock:

- place patient in recumbent position with legs raised

- rapidly substitute volume with e.g. isotonic electrolyte solution (pressure infusion), plasma expanders

- immediately administer 0.1-0.5 mg adrenaline (epinephrine) diluted to 10 ml with 0.9 % saline intravenously (repeat after 10 minutes if necessary)”

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 suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

No cases of overdose have been reported.