4.1. Therapeutic indications

This medicinal product is for diagnostic use only.

For fluorescein angiography of the ocular fundus.

4.2. Posology and method of administration

Posology

Adults, including elderly

Inject 5 ml of Anatera 100 mg/ml solution for injection rapidly into the antecubital vein after taking precautions to avoid extravasation. In cases when highly sensitive imaging systems e.g., scanning laser ophthalmoscope are used, the dose of this product should be reduced to 2 ml of Anatera 100 mg/ml solution for injection.

Paediatric population

Anatera 100 mg/ml solution for injection has not been studied in children and dose-adaptation data are not available. Therefore, Anatera 100 mg/ml solution for injection should not be used in patients below 18 years as efficacy and safety in this group have not been established.

Patients with renal insufficiency (glomerular filtration rate below 20 ml/min):

Limited experience in renally impaired subjects (glomerular filtration rate below 20 ml/min) suggests that, in general, no dose adjustment is required although a longer excretion rate in patients with renal impairment is possible (see section 5.2).

Dialysed patients: Reduce dose to 2.5 ml (half a vial).

Method of administration and fluorescence angiography

Anatera 100 mg/ml solution for injection should be used exclusively by qualified physicians with technical expertise in performing and interpreting fluorescence angiography.

This product should only be administered intravenously.

Flush intravenous cannulas with sterile sodium chloride solution (0.9%) before and after medicinal products are injected to avoid physical incompatibility reactions. The injection should be administered rapidly (1 ml per second is normally recommended) into the antecubital vein, after taking precautions to avoid extravasation using a 23 gauge butterfly needle for injection. Luminescence usually appears in the retina and choroidal vessels in 7 to 14 seconds.

For further instructions on the correct administration/use of the medicinal product, see sections 6.2 and 6.6.

4.3. Contraindications

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

Anatera 100 mg/ml solution for injection should not be injected intrathecally or intra-arterially.

4.4. Special warnings and precautions for use

Fluorescein sodium can induce serious intolerance reactions.

In the event of serious intolerance reactions during a first angiography, the benefit of an additional fluorescein angiography should be balanced with the risk of severe hypersensitivity reactions (with fatal outcome in some cases).

These reactions of intolerance are always unpredictable but they are more frequent in patients who have previously experienced an adverse reaction after fluorescein injection (symptoms other than nausea and vomiting) in patients with history of allergy such as food or drug induced urticaria, asthma, eczema, allergic rhinitis or in patients with history of bronchial asthma.

Intradermal skin tests are not reliable in predicting these intolerance reactions and so their use can be dangerous. A specialized allergy consultation should be undertaken to make this diagnosis.

The benefit to risk of the angiography procedure should be considered in patients with pre-existing conditions such as cardiovascular disease, diabetes mellitus, and multiple concomitant drug therapies. (in particular beta-blockers, see section 4.5).

Any pre-existing systemic condition(s) impacting renal function could pose additional risk to the subject. The physician must exercise medical judgement based on increased serum creatinine, patient's age, medical history, and current health status to determine potential risk vs benefit prior to use of Fluorescein.

Literature suggests Fluorescein Angiography (FA) may cause contrast-induced Nephropathy (CIN) based on increased serum creatinine. CIN is a possible risk factor for end-stage renal disease progression.

Detailed questioning of each patient must be carried out before the angiography to search for any history of cardiopulmonary disease or allergy or concomitant medications (such as beta-blocking agents, including eye-drops solutions) (see section 4.5). If the examination appears to be really necessary for a patient identified as being at risk of hypersensitivity reactions and for a patient treated with beta-blocking agents (including eye-drops solutions), this examination should be performed under the supervision of a physician experienced in intensive care (resuscitation). Beta-blocking agents could reduce the vascular compensation reactions to anaphylactic shock and reduce the effectiveness of adrenaline in the case of cardiovascular collapse. Before any fluorescein sodium injection, the physician should seek information about concomitant treatment with a beta-blocking agent.

Premedication can be undertaken. However, the risk of occurrence of severe adverse drug reactions still remains. Premedication includes mainly oral antihistaminic H1 drugs, followed by corticosteroids, before injection of fluorescein. Given the low incidence of these adverse reactions, such pre-medication is not recommended for all patients.

The risk of hypersensitivity reactions with fluorescein sodium requires:

• Close monitoring of the patient by the ophthalmologist performing the examination, throughout the examination and for at least 30 minutes after;

• Maintaining the infusion line for at least 5 minutes, to treat a possible severe adverse reaction without delay;

• To have at one's disposal appropriate material for emergency resuscitation which is based at first on the installation of a 2nd intravenous line, allowing the restoration of the plasma volume (aqueous solution polyionic or colloidal substitute of plasma) and the intravenous injection of adrenaline at the recommended dosage (see section 4.5).

Note:

Extravasation should be avoided due to the high pH of fluorescein solution which can result in severe local tissue damage (severe pain in the arm for several hours, sloughing of the skin; superficial phlebitis). The correct intravenous position of the needle tip must be ascertained. When extravasation occurs, the injection should be immediately discontinued. Appropriate measures must be taken to treat damaged tissue and to relieve pain.

If an X-ray procedure is conducted within 36 hours of injection (maximum duration of fluorescein elimination from the body), the resultant high visibility of the excretory organs in the X-ray image may lead to misinterpretation.

This medicinal product contains 72.45 mg sodium per 5 ml vial, equivalent to 3.7% of the WHO recommended maximum intake of 2 g sodium for an adult.

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

Fluorescein is a relatively inert dye and specific drug interaction studies have not been reported. There are few case reports on potential interactions with organic anion transporters and interference with certain laboratory tests. It is possible that fluorescein may influence certain blood and urine values for 3 to 4 days after application. Caution is advised when performing therapeutic drug monitoring for drugs with a narrow therapeutic window, e.g. digoxin, quinidine. Compounds that inhibit or compete with the active transport of organic anions (e.g., probenicid) may affect the systemic profile of fluorescein.

The concomitant use of Anatera 100 mg/ml solution for injection with beta-blocking agents (including eye- drops solutions) may rarely provoke severe anaphylactic reactions.

Beta-blocking agents could reduce the vascular compensation reactions to anaphylactic shock and also reduce the effectiveness of adrenaline in the presence of cardiovascular collapse that may require intensive pharmacologic therapy and even resuscitative measures (see section 4.4).

Concomitant intravenous injection of other solutions or the mixing of Anatera 100 mg/ml solution for injection with other solutions should be avoided as the possibility of interactions cannot be excluded.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited data available concerning the use of Anatera 100 mg/ml solution for injection in pregnancy. Animal studies do not indicate teratogenic effects (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Anatera 100 mg/ml solution for Injection during pregnancy.

Breast-feeding

Fluorescein sodium is excreted in human milk following systemic administration for up to 7 days. A risk to the suckling child cannot be excluded. Following fluorescein angiography, breast-feeding should therefore be discontinued for 7 days and the milk should be pumped off and discarded during this period.

Fertility

Studies have not been performed to evaluate the effect of intravenous administration of fluorescein on fertility.

4.7. Effects on ability to drive and use machines

If mydriasis is necessary for the examination with fluorescence angiography visual acuity is influenced and thus affects the ability to react in traffic or use machinery. The patient must be made aware that after application and until visual acuity returns to normal, driving a vehicle or operating dangerous machinery is prohibited.

4.8. Undesirable effects

Summary of safety profile

The most frequently reported treatment related undesirable effects were nausea, vomiting, syncope and pruritus. Less frequent but more severe adverse reactions have been reported shortly after fluorescein injection such as: angioedema, respiratory disorders (bronchospasm, laryngeal oedema, and respiratory failure), anaphylactic shock, hypotension, loss of consciousness, convulsion, respiratory arrest, and cardiac arrest.

Tabulated list of adverse reactions

The following adverse reactions were assessed to be treatment-related and are classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Classification

MedDRA Preferred Term (v27.1.)

Immune system disorders

Uncommon: hypersensitivity

Rare: anaphylactic reaction

Very rare: anaphylactic shock

Nervous system disorders

Common: syncope

Uncommon: dysphasia, paraesthesia, dizziness, headache

Very rare: convulsion

Not known: cerebrovascular accident , vertebrobasilar insufficiency, loss of consciousness, tremor, hypoaesthesia, dysgeusia,

Cardiac disorders

Rare: cardiac arrest

Very rare: angina pectoris, bradycardia, tachycardia

Not known: myocardial infarction,

Vascular disorders

Uncommon: thrombophlebitis

Rare: hypotension, shock

Very rare: hypertension, vasospasm, vasodilatation, pallor, hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon: cough, throat tightness

Rare: bronchospasm

Very rare: respiratory arrest, pulmonary oedema, asthma, laryngeal oedema, dyspnoea, sneezing, nasal oedema

Not known: throat irritation

Gastrointestinal disorders

Very common: nausea

Common: abdominal discomfort, vomiting

Uncommon: abdominal pain

Not known: retching, diarrhoea

Skin and subcutaneous tissue disorders

Common: pruritus

Uncommon: urticaria

Not known: rash, cold sweat, eczema, erythema, hyperhidrosis, skin discolouration

General disorders and administration site conditions

Common: extravasation

Uncommon: pain, feeling hot

Not known: chest pain, oedema, malaise, asthenia, chills

Description of selected adverse reactions

A yellowish discolouration of the skin could appear but usually disappears within 6 to 12 hours. Urine, which may also exhibit a bright yellow colouration, returns to its normal colour after 24 to 36 hours.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of benefit/risk balance of the medicinal product. Health care professionals are asked to report any suspected adverse reactions via their national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

No toxic effects are expected given the minimal risk of overdose with Anatera 100 mg/ml solution for Injection.