Anatera 100 mg/ml solution for injection

1 ml solution contains 100 mg fluorescein (as 113.2 mg fluorescein sodium)

One 5 ml vial contains 500 mg fluorescein (as 566 mg fluorescein sodium)

Contains sodium (from fluorescein sodium and sodium hydroxide) at amounts up to 1.45% (approximately 3.15 mmol), per dose.

For a full list of excipients, see section 6.1.

Solution for injection

Clear, red-orange solution

This medicinal product is for diagnostic use only.

For fluorescein angiography of the ocular fundus.

Posology

Use in adults, including the elderly:

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.

Use in pediatric patients:

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.

Use in 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 this product, see sections 6.2 and 6.6.

Hypersensitivity to the active substance or to any of the excipients.

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

Fluorescein sodium can induce serious intolerance reactions.

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). If the examination appears to be really necessary 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.

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) or in patients with history of allergy such as food or drug induced urticaria, asthma, eczema, allergic rhinitis. 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.

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). When extravasation occurs, the injection should be immediately discontinued.

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 up to 3.15 mmol (72.45 mg) sodium per dose. This should be taken into consideration by patients on a controlled sodium diet.

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. 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 (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.

It is possible that fluorescein may influence certain blood and urine values for 3 to 4 days after application.

Pregnancy

There are insufficient 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). However, due to limited experience, caution should be exercised when considering the use of Anatera 100 mg/ml solution for injection during pregnancy.

Lactation

Fluorescein sodium is excreted in human milk for up to 4 days. Following fluorescein angiography, breast-feeding should therefore be discontinued for 4 days and the milk should be pumped off and discarded during this period.

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.

The most frequently reported treatment related undesirable effects were nausea, vomiting, syncope and pruritis. More severe adverse reactions have been reported shortly after fluorescein injection such as angioedema, respiratory disorders (bronchospasm, laryngeal oedema, respiratory failure), anaphylactic shock, hypotension, respiratory arrest and cardiac arrest.

Additionally, a yellowish discoloration 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.

The following undesirable effects 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 1/1000), or very rare (1/10,000). Within each frequency grouping, undesirable effects are presented in decreasing order of seriousness.

Immune system disorders:

Uncommon: hypersensitivity

Rare: anaphylactic reaction

Very Rare: anaphylactic shock

Nervous system disorders:

Common: syncope

Uncommon: paresthesia, dizziness, headache

Very Rare: convulsion

Not Known: vertebrobasilar insufficiency

Cardiac disorders:

Rare: cardiac arrest

Very Rare: angina pectoris, bradycardia, tachycardia

Vascular disorders:

Uncommon: thrombophlebitis

Rare: hypotension, shock

Very Rare: hypertension, vasospasm, vasodilation, pallor, hot flush

Respiratory, thoracic and mediastinal disorders:

Uncommon: cough, throat tightness

Rare: bronchospasm

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

Gastrointestinal disorders:

Very Common: nausea

Common: abdominal discomfort, vomiting

Uncommon: abdominal pain

Skin and subcutaneous tissue disorders:

Common: pruritus

Uncommon: urticaria

General disorders and administration site conditions:

Common: extravasation

Uncommon: dysphasia, pain, feeling hot

No case of overdose has been reported.

Pharmacotherapeutic group: DIAGNOSTIC AGENTS, Colouring agents

ATC code: S01JA01

Fluorescein sodium is a fluorochrome used in medicine as a diagnostic stain. Fluorescein is used to make the blood vessels of the ocular fundus visible (angiography of the retina and choroid).

Distribution:

Within 7 to 14 seconds after intravenous administration into antecubital vein, fluorescein usually appears in the central artery of the eye. Within a few minutes of intravenous administration of fluorescein, a yellowish discoloration of the skin occurs, which begins to fade 6 to 12 hours after dosing. Various estimates of volume of distribution indicate that fluorescein distributes well into interstitial space (0.5 L/kg).

Metabolism:

Fluorescein undergoes rapid metabolism to fluorescein monoglucuronide. After intravenous administration of fluorescein sodium (14 mg/kg) to 7 healthy subjects, approximately 80% of fluorescein in plasma was converted to glucuronide conjugate after a period of 1 hour post dose, indicating relatively rapid conjugation.

Excretion:

Fluorescein and its metabolites are mainly eliminated via renal excretion. After intravenous administration, the urine remains slightly fluorescent for 24 to 36 hours. A renal clearance of 1.75 ml/min/kg and a hepatic clearance (due to conjugation) of 1.50 ml/min/kg have been estimated. The systemic clearance of fluorescein is essentially complete by 48 to 72 hours after administration of 500 mg fluorescein. Although a longer excretion rate in patients with renal impairment is possible, limited experience in renally impaired subjects (glomerular filtration rate below 20 ml/min) suggests that, in general, no dose adjustment is required.

Non-clinical data for sodium fluorescein reveal no special hazard for humans based on studies of single dose toxicity.

Fluorescein did not show teratogenic effects in rats and rabbits. Fluorescein crosses the placental barrier. After the intravenous application of 500 mg/kg intense fluorescence was detectable both in the fetus and the amniotic fluid.

Studies on mutagenicity did not show any mutagenic effects of fluorescein sodium

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid (for pH-adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

To avoid physical incompatibilities, this product must not be administered simultaneously with other solutions for injection with acid pH (especially antihistamines) by the same intravenous route (see section 4.2 for information about cannulas).

Once opened the vial must be immediately used.

2 years

Do not store above 25°C.

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

Glass (type I) vial with grey chlorobutyl coated rubber stopper and aluminum seal with polypropylene flip-off cap.

Pack containing 12 vials of 5 ml injection solution

The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles. For single use only. Any unused product or waste material should be disposed of in accordance with local requirements. Do not use Anatera 100 mg/ml solution for injection if the vial is cracked or damaged in any way.

Alcon Laboratories (UK) ltd

Pentagon Park

Boundary Way

Hemel Hempstead

Herts HP2 7UD

PL 00649/0377

24/04/2008

11/02/2009