SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nanotop 0.5 mg Kit for radiopharmaceutical preparation

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains 0.5 mg human albumin, colloidal particles.

At least 95 % of ^99mTc nano-sized albumin colloidal particles have a diameter < 80 nm.

The radionuclide is not part of the kit.

Excipient(s) with known effect:

Sodium: 0.009 mmol (0.2 mg) per vial.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparation White or almost white lyophylisate Powder for suspension for injection

For radiolabelling with Sodium f^9mTc)pertechnetate solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only. After radiolabelling with Sodium pertechnetate f^9mTc) solution, "^mTc nano-sized albumin colloid obtained may be used for:

Subcutanous administration:

•    Lymphatic scanning to demonstrate the integrity of the lymphatic system and differentiation of venous from lymphatic obstruction

•    Sentinel node detection in:

-    Malignant melanoma

-    Breast cancer

Posology

Adults

Subcutaneous administration:

Lymphoscintigraphy by single or multiple subcutaneous (interstitial) injection:

18.5 - 110 MBq per injection site. The activity to be administered depends on the anatomical areas to be investigated and upon the time interval between injection and imaging. The injected volume should not exceed 0.2 - 0.3 ml per injection site. A maximum volume of more than 0.5 ml per injection site must not be applied.

The injection is administered subcutaneously, after confirmation by aspiration that no blood vessel was inadvertently punctured.

Sentinel node detection:

-    Malignant Melanoma: The recommended dose varies from 10 to 110 MBq, using intradermal injection of the radiocolloid, producing 2-4 wheals surrounding the tumor/scar. The total activity to be injected should be adjusted to the time course of the Sentinel Node Biopsy.

-    Breast Cancer: [Product name] can be administered with intradermal, subdermal or periareoral injection in the presence of superficial tumor (palpable lesions); intratumoral or interstitial peritumoral injection should be performed in deep tumors (non-palpable lesions).

Total activities vary from 5 to 200 MBq depending on the elapsed time between scintigraphy and surgery.

A single injection in small volume (0.2 ml) is recommended.

Multiple injections or higher activities may be used in particular circumstances/conditions taking into account the sensitivity of the detection probes.

Dosage reductions in renal or hepatic impairment are not necessary.

Pediatric population

Lymphoscintigraphy in children and adolescents has to be considered carefully, based upon clinical needs and assessing the risk/benefit ratio in this patient group. The activity for children should be calculated from the recommended range of adult activity and adjusted according to body weight and body surface area. However the Paediatric Task Group of the European Association of Nuclear Medicine (EANM) recommends calculating the administered activity from the body weight according to the following table as a fraction of activity for the adult.

Body weight (kg)	Part of adult dose	Body weight (kg)	Part of adult dose
3	0.1	32	0.65
4	0.14	34	0.68
6	0.19	36	0.71
8	0.23	38	0.73
10	0.27	40	0.76
12	0.32	42	0.78
14	0.36	44	0.80
16	0.40	46	0.82
18	0.44	48	0.85

Body weight (kg)	Part of adult dose	Body weight (kg)	Part of adult dose
20	0.46	50	0.88
22	0.50	52 - 54	0.90
24	0.53	56 - 58	0.92
26	0.56	60 - 62	0.96
28	0.58	64 - 66	0.98
30	0.62	68	0.99

For use in children, it is possible to dilute the product up to 1:50 with 0.9 % sodium chloride injection.

Method of Administration

This medicinal product should be reconstituted before administration to the patient. For instructions on reconstitution of the medicinal product before administration, see section 12.

This product is not intended for regular or continuous administration.

Shake the radiolabelled injection suspension (^99mTc albumin nano-sized colloid) immediately before withdrawal of the patient dose from the vial. Swivel the syringe several times before the injection.

Image acquisition

•    Conventional lymphoscintigraphy: The injection is given subcutaneously, after checking by aspiration, that a blood vessel has not been inadvertently punctured. When imaging the lower limbs, dynamic pictures are taken immediately following injection and static imaging 30-60 minutes later. In parasternal lymph scanning, repeated injections and additional images may be required.

•    Sentinel node detection:

o Malignant Melanoma: Lymposcintigraphic images are obtained starting after injection and regularly thereafter until the SLN is visualized. o Breast Cancer: Scintigraphic scans of breast and axillary region can be acquired 15-30 min and 3 hours after injection.

For patient preparation, see section 4.4.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in 6.

In particular, the use of ^99mTc-human albumin colloidal particles is contraindicated in persons with a history of hypersensitivity to products containing human albumin.

In patients with complete lymph obstruction lymph node scintigraphy is not advisable because of the danger of radiation necroses at the site of injection. Pregnancy.

Potential for hypersensitivity or anaphylactic reactions If hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product must be discontinued immediately and if necessary, intravenous treatment initiated. To enable immediate action in emergencies, the necessary medicinal products and equipment such as endotracheal tube and ventilator must be immediately available.

Individual benefit/risk justification

For each patient, exposure to ionising radiation must be justifiable on the basis of likely diagnostic benefit and risk from radiation exposure. The activity administered must be such that the resulting radiation dose is as low as reasonably achievable, bearing in mind the need to obtain the intended diagnostic information.

Radionuclide procedures carried out on pregnant women also involve radiation dose to the foetus. Only essential investigations should therefore be carried out during pregnancy/breastfeeding, when the likely benefit far exceeds the risk incurred by the mother and foetus.

Paediatric population

For information on the use in paediatric population and adolescents, see section 4.2.

Patient preparation

The patient should be well hydrated before the start of the examination and urged to void as often as possible during the first hours after the study in order to reduce radiation exposure.

Further remarks

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection, and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded.

This also applies to unknown or emerging viruses and other pathogens.

There are no reports of virus transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes.

It is strongly recommended that every time that Nanotop 0.5 mg Kit for radiopharmaceutical preparation is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Warnings related to excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Iodinated contrast media used in lymphoangiography may interfere with lymphatic scanning using ^99mTc nano-sized albumin colloid.

Women of childbearing potential

When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient.

Pregnancy

Radionuclide procedures carried out on pregnant women also involve radiation dose to the foetus. Only essential investigations should therefore be carried out during pregnancy, when the likely benefit far exceeds the risk incurred by the mother and foetus.

During pregnancy the subcutaneous administration of technetium 99m albumin nanocolloid for lymphoscintigraphy is strictly contraindicated, due to the possible accumulation in pelvic lymph nodes.

Breast feeding

Before administering radiopharmaceuticals to a mother who is breastfeeding consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breastfeeding, and to what is the most appropriate choice of radiopharmaceuticals, bearing in mind the secretion of activity in breast milk.

If the administration is considered necessary, breastfeeding should be interrupted for 13 hours and the expressed feeds discarded.

Fertility

There are no data available.

4.7 Effects on ability to drive and use machines

The product has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

During the evaluation of side effects the following frequency data are taken as a basis:

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)

not known (cannot be estimated form the available data)

Very rare:

slight and temporary hypersensitivity reactions, which can express symptoms

at the administration area/skin local reactions, rash, itching as immune system disease vertigo, hypotension other diseases

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 2.3 mSv when the maximal recommended activity of 500 MBq is administered these adverse events are expected to occur with a low possibility.

When a protein-containing radiopharmaceutical such as ^99mTc-Nanotop is administered to a patient, hypersensitivity reactions may develop.

For safety with respect to transmissible agents see section 4.4.

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

In the event of an overdose of radioactivity being administered, no practical measure can be recommended to satisfactorily diminish tissue exposure as the ^99mTc nano-sized albumin colloid is poorly eliminated in urine and faeces.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Technetium (99mTc) nanocolloid (ATC-code: V09DB01)

At the chemical concentrations and activities used for diagnostic procedures technetium-99m - albumin colloidal particles do not appear to exert any pharmacodynamic effects.

5.2 Pharmacokinetic properties

Nanotop is a nano-sized colloid from human serum albumin. 95 % of the particles are smaller than 80 nm (determined by filtration).

After subcutaneous injection into connective tissue, 30-40 % of the administered technetium-99m albumin colloidal particles (less than 100 nm) are filtered into lymphatic capillaries whose main function is the drainage of proteins from the interstitial fluid back into the blood pool. The technetium-99m albumin colloidal particles are then transported along the lymphatic vessels to regional lymph nodes and main lymphatic vessels, and are finally trapped into the reticular cells of functionary lymph nodes. A fraction of the injected dose is phagocytised by histiocytes at the injection site. Another fraction appears in the blood and accumulates mainly in the reticuloendothelial system (RES) of the liver, spleen and bone marrow; faint traces are eliminated via the kidneys.

5.3 Preclinical safety data

No animal death and no gross pathological changes at necropsy were noted after intravenous injection of 800 and 950 mg in mice and rats respectively. No local reactions were observed in either mice or rats following subcutaneously injection of 1 g albumin colloidal particles /kg body weight, reconstituted with 0.9 % saline injection.

These doses correspond to the contents of 50 vials per kg body weight, which is the 3,500-fold compared to the maximum human dose.

Mutagenicity studies and long-term carcinogenicity studies have not been carried out.

Reproductive toxicity studies are not available.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Stannous chloride, dihydrate

Glucose

Poloxamer 238

Disodium phosphate dihydrate, E339 Sodium phytate

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6 and 12.

6.3 Shelf life

24 months

After radiolabelling: 6 hours. Do not store above 25°C after radiolabelling.

Do not store above 25 °C.

For storage conditions after radiolabelling, see section 6.3.

Store in the original package in order to protect from light.

Storage of radiopharmaceuticals should be in accordance with national regulation on radioactive materials.

6.5 Nature and contents of container

10 ml nominal capacity, multi-dose borosilicate glass vials (Type I Ph. Eur.) sealed with a synthetic rubber stopper and an aluminium crimp cap.

Pack size:    5 vials

6.6 Special precautions for disposal

General warning

After radiolabelling of Nanotop the common protective measures for radioactive medicinal product must be applied.

Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the competent official organisation.

Radiopharmaceuticals should be prepared by the user in a manner which satisfies both radiation safety and pharmaceuticals quality requirements. Appropriate aseptic precautions should be taken.

Contents of the vial are intended only for use in the preparation of ^99mTc-albumin colloidal particles and are not to be administered directly to the patient without first undergoing the preparative procedure.

For instructions on radiolabelling of the medicinal product before administration, see section 12.

If the integrity of this vial is compromised, the product should not be used. The content of the kit before radiolabelling is not radioactive. However, after sodiumpertechnetate (^9mTc), Ph. Eur. is added, adequate shielding of the final preparation must be maintained.

The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from excretions of the patient. Therefore appropriate radiation protection precautions in accordance with national regulations must be taken.

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

7 MARKETING AUTHORISATION HOLDER

ROTOP Pharmaka AG Bautzner LandstraBe 400

organ (injection site) is 183 mGy and to the target organ (lymph nodes) 8.1 mGy.

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

The content of the kit before preparation is not radioactive. However, after Sodium Pertechnetate (^99mTc) solution Ph. Eur. is added, adequate shielding of the final preparation must be maintained.

^99mTc-Nanotop is to be used within six (6) hours from radiolabelling.

If the integrity of this vial is compromised, the product should not be used.

This agent is not intended for regular or continuous administration.

Method of preparation

Nanotop does not contain preservatives.

Aseptic preparation and the attention of the radiation protection are necessary. The formation of the ^99mTc nano-sized albumin colloid depends on a sufficient content of tin in the reduced state. Oxidation can affect the quality of the preparation. Air inlet has to be strictly avoided.

The specific activity of the applied ^99mTc nano-sized albumin colloid should be as high as possible, since only approx. 1 - 2 % of the activity is enriched in lymph nodes after subcutaneous administration. Therefore it is recommended to use fresh eluate of a generator eluted shortly before the radiolabelling. Labelling should be accomplished with the highest possible activity shortly before administration.

For use in children, it is possible to dilute the product up to 1:50 with 0.9 % sodium chloride injection.

Radiochemical marking / preparation of an injection suspension

1.    Place the vial in a suitable lead shield.

2.    Add 185 to 5,550 MBq in 1 - 5 ml of sodium pertechnetate (^99mTc) solution into the vial using a sterile syringe.

Then withdraw the same volume of nitrogen from the vial using the same syringe for pressure compensation. Do not use a breather needle.

3.    Dissolve the dry substance by repeated inverting; allow to stand for 10 min at room temperature.

4.    Shake the injection suspension immediately before withdrawing a dose from the vial. Shake the syringe several times before injection.

Characteristics of the ready to use suspension

Volume    1 - 5 ml

colour    clear, colourless

particles    more    than    95    %    smaller    than    80 nm

radiolabelled colloid > 95 %

pH-value    7 to 8

Test for labelling yield

The radiochemical purity of the ready to use injection suspension can be controlled by thin layer chromatography.

Method A:

TLC plate    KG 60

Running distance 10 - 15 cm Development time 15 - 20 minutes

99mi

[ Tc]pertechnetate can be found near the solvent front.

The ready to use injection suspension should not contain more than 5 % free [^99mTc]pertechnetate and must be used within 6 hours.

(Alternative) Method B:

TLC plate

Solvent

Running distance 5 cm Development time 5 - 10 minutes ^99mTc nano-sized albumin colloid remains at the start, free [^99mTc]pertechnetate can be found near the solvent front.

The ready to use injection suspension should not contain more than 5 % free [^99mTc]pertechnetate and must be used within 6 hours.