SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

NANOCOLL 500 micrograms kit for radiopharmaceutical preparation.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Human albumin colloidal particles 500 micrograms/vial.

At least 95% of human albumin colloidal particles have a diameter < 80 nm. NANOCOLL is prepared from human serum albumin derived from human blood donations tested according to the EEC Regulations and found non reactive for:

-    hepatitis B surface antigen (HBsAg)

-    antibodies to human immunodeficiency virus (anti-HIV 1/2)

-    antibodies to hepatitis C virus (anti-HCV)

NANOCOLL is reconstituted with Sodium Pertechnetate (^99mTc) Injection (not included in this kit) to prepare technetium-99m albumin nanocolloid injection.

Technetium-99m decays with the emission of gamma radiation with an energy of 140 keV and a half life of 6 hours to technetium-99 which can be regarded as quasi stable.

Excipients with known effect:

The reconstituted injection contains 0.24 mg/ml sodium.

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparation.

Powder for solution for injection.

4.1    Therapeutic indications

This medicinal product is for diagnostic use only.

After reconstitution with Sodium Pertechnetate (^99mTc) Injection the product is indicated in adults, neonates and children aged 1 to 18 years for:

-    Bone marrow scanning. (The product is not suitable to study the haematopoietic activity of the bone marrow).

-    Inflammation scanning in areas other than the abdomen.

Local administration:

Lymphoscintigraphy to demonstrate integrity of the lymphatic system, to differentiate between venous and lymphatic obstructions, and to identify the sentinel lymph node draining a primary tumour in the following malignant diseases: melanoma, breast, prostate, penile, head and neck and female pelvic (cervical and vulvar) cancer.

4.2. Posology and method of administration

Posology

Adults

Bone Marrow and Inflammation Imaging

Recommended activities in adults are as follows:

Bone marrow scanning: 185-500 MBq.

Inflammation imaging: 370-500 MBq.

Lymphoscintigraphy and Sentinel Lymph Node Imaging

Recommended activities in adults are as follows:

Lymphoscintigraphy: The recommended activity by single or multiple injections ranges from

5-400 MBq, depending on the anatomical area to be investigated and the time interval between injection and imaging. Higher doses are required where the interval between injection and imaging is longer. For detailed sentinel node identification recommendations, see below.

•    Melanoma: 5-120 MBq

•    Breast Cancer: 5-370 MBq

•    Prostate Cancer: 90-400 MBq

•    Squamous cell carcinoma of the penis: 40-131 MBq

•    Head and Neck Cancer: 15-120 MBq

•    Female Pelvic Cancer:

o cervical (stage Ia2/Ib1, IIa1): 110 MBq

o endometrial (stage I and II high-risk endometrial cancer, ie, endometrioid cancer with the following: more than 50 % myometrial invasion or poorly differentiated (grade 3) or serous papillary, clear-cell or carcinosarcoma histological subtype): 40-185 MBq

o vulvar (squamous cell vulvar carcinoma Ib/II less than 4 cm in size, without presurgical nodal metastases): 20-150 MBq

Renal and hepatic impairment

Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in these patients.

Paediatric population

The use 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 may be calculated from the recommended range of adult activity and adjusted according to body weight or surface area. However the Paediatric Task Group of the European Association of Nuclear Medicine (EANM) recommends to calculate the administered activity from the body weight according to the following table.

Fraction of adult dose:

3 kg = 0.10	22 kg = 0.50	42 kg = 0.78
4 kg = 0.14	24 kg = 0.53	44 kg = 0.80
6 kg = 0.19	26 kg = 0.56	46 kg = 0.82
8 kg = 0.23	28 kg = 0.58	48 kg = 0.85
10 kg = 0.27	30 kg = 0.62	50 kg = 0.88
12 kg = 0.32	32 kg = 0.65	52-54 kg = 0.90
14 kg = 0.36	34 kg = 0.68	56-58 kg = 0.92
16 kg = 0.40	36 kg = 0.71	60-62 kg = 0.96
18 kg = 0.44	38 kg = 0.73	64-66 kg = 0.98
20 kg = 0.46	40 kg = 0.76	68 kg = 0.99

In very young children (up to 1 year) a minimum dose of 20 MBq (bone marrow scanning) is necessary in order to obtain images of sufficient quality.

In children it is possible to dilute the product, see section 12. This product is not intended for regular or continuous administration.

Method of administration

This medicinal product must be radiolabelled before administration to the patient. Intravenous administration:

-    Bone marrow scanning: Images may be acquired 45-60 minutes after administration.

-    Inflammation imaging: Dynamic imaging is performed immediately.

Static imaging comprises an early phase, 15 minutes post-injection and a washout phase, 30-60 minutes post-injection.

To demonstrate integrity of the lymphatic system and to differentiate between venous and lymphatic obstructions, Nanocoll is generally given by single or multiple subcutaneous (interstitial) injection (5-110 MBq per injection site), depending 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. A maximum volume of 0.5 ml per injection is critical.

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.

For sentinel node identification specific recommendations are given below. Dual mapping with blue dye may increase sensitivity and decrease false-negative rate.

•    Melanoma: dose 5-120 MBq, divided into volumes of 0.1-0.2 ml, with between 1 and 8 intradermal injections administered, depending on the location of the lesion and the timing of the injection (eg, 4-8 injections for head-neck and trunk lesions, or wide excisions/large lesions, administered roughly equatorially, around the lesion, and 2 injections for smaller lesions on the extremities, given medial and lateral to the tumour/scar).

•    Breast cancer: dose 5-370 MBq. When using superficial (periareolar, subdermal, intradermal, or subareolar) injections, large volumes of injectate may interfere with normal lymphatic flow; therefore, volumes of 0.05-0.5 mL are recommended. With peritumoral injections, larger volumes (e.g. 0.5-1.0 mL) may be used.

•    Prostate cancer: dose 90-400 MBq, injected transrectally into the prostate with ultrasound guidance, with total dose split into aliquots to be administered to each lobe.

•    Squamous cell carcinoma of the penis: dose 40-131 MBq, administered in aliquots intradermally, into or around the tumour, under local anaesthesia.

•    Head and Neck Cancer: dose 15-120 MBq, administered in two to four aliquots, according to the size and location of the lesion, submucosally for lesions in sites with abundant soft tissue (eg, soft palate or floor of the mouth), or to the depth of the lesion for those located in muscle (eg, tongue).

•    Female Pelvic Cancer: in cervical cancer the product is injected peritumorally/periorificially into the four quadrants of the cervix. In endometrial cancer the following approaches may be used: cervical (periorificially into the four quadrants of the cervix), or myometrial/subserosal injection (guided by transvaginal ultrasonography). In vulvar cancer three or four intradermal/intramucous peritumoral injections may be given under local anaesthesia.

For instructions for preparation and control of the radiochemical purity of the radiopharmaceutical, see section 12.

For patient preparation, see section 4.4.

Image acquisition

Dynamic or delayed image acquisition should be performed according to local practice.

4.3 Contraindications

Hypersensitivity to the active substance(s), to any of the excipients listed in section 6.1, or to any of the components of the labelled radiopharmaceutical. In particular, the use of ^99mTc-human albumin colloidal particles is contraindicated in persons with a history of hypersensitivity to products containing human albumin.

During pregnancy, lymphoscintigraphy, including sentinel node detection, involving the pelvis is strictly contraindicated due to the accumulation in lymph nodes.

4.4 Special warnings and precautions for use

Paediatric population

Paediatric population, see section 4.2.

Individual benefit / risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required diagnostic information.

Lymphoscintigraphy is not advised in patients with total lymphatic obstruction because of the potential radiation hazard at injection sites.

The limitations of Nanocoll in sentinel lymph node identification include:

•    Unusual drainage patterns may be detected, especially in patients who have had previous surgery or radiotherapy.

•    The nearest node may not be on direct path and a potential secondary node may be involved with metastasis. All detected nodes should be assessed.

•    Lower success rates are possible in secondary biopsies after surgery.

•    In gynaecological cancer, Nanocoll is not recommended for patients with suspected extrauterine involvement, in the presence of pathological pelvic or paraaortic lymph nodes on radiological examination, and in cases of a previous history of surgery or radiotherapy to nodal areas under study. Caution should be taken with midline vulvar tumours, which may drain bilaterally.

•    In oral squamous carcinoma failure to detect sentinel nodes may be related to incorrect injection technique or close proximity of sentinel nodes to the injection site (eg, floor of mouth tumours). In addition, metastatic deposits may block lymphatic drainage causing nonvisualization of sentinel nodes. A repeat injection and imaging procedure, or preferably neck dissection should be considered.

Renal impairment and hepatic impairment

Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is possible.

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.

Potential for hypersensitivity or anaphylactic reactions The possibility of hypersensitivity including serious, life-threatening, fatal anaphylactic/ anaphylactoid reactions should always be considered. If hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product must be discontinued immediately and intravenous treatment initiated, if necessary. To enable immediate action in emergencies, the necessary medicinal products and equipment such as endotracheal tube and ventilator must be immediately available.

Specific warnings

It is strongly recommended that the product name and batch number are stated every time Tc-albumin nanocolloid is given to a patient, in order to maintain a connection between the patient and the product’s batch number.

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.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A and parvovirus B19 viruses.

There are no reports of virus transmission in connection with albumin, made in accordance with specifications in Ph. Eur. and in accordance with routine processes.

Precautions with respect to environmental hazard are in Section 6.6.

Before reconstitution this medicinal product contains less than lmmol sodium (23mg) per vial, i.e. essentially ‘sodium-free’. The reconstituted injection contains 0.24 mg/ml sodium. This needs to be taken into consideration for patients on a controlled sodium diet.

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

Iodinated contrast media used in lymphoangiography may interfere with lymphatic scanning using technetium-99m albumin nanocolloid.

Fertility, pregnancy and lactation

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 doses to the foetus. Only essential investigations should therefore be carried out during pregnancy, when the likely benefit far exceeds the risk incurred by mother and foetus.

Dose to the uterus arising for intravenous administration of 500 MBq of (^99mTc) albumin nanocolloid is 0.9 mGy. Dose to the uterus above 0.5 mGy will be regarded as a potential risk to the foetus.

During pregnancy the subcutaneous administration of (^99mTc) albumin nanocolloid for lymphoscintigraphy, including sentinel node detection, is strictly contraindicated, due to the possible accumulation in pelvic lymph nodes, see section 4.3.

Breastfeeding

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 as to what is the most appropriate choice of radiopharmaceutical, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, breastfeeding should be interrupted for 13 hours post injection and the expressed feeds discarded.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.7 Undesirable effects

The frequencies of undesirable effects are defined as follows:

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) and not known (cannot be estimated from the available data)

Occasionally hypersensitivity reactions (including very rare life-threatening anaphylaxis) may occur.

Immune system disorders

Not known: Hypersensitivity, anaphylaxis

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 probability.

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 United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

In the event of an overdose of radioactivity being administered when using technetium-99m albumin nanocolloid, no practical measure can be recommended to satisfactorily diminish tissue exposure as the label is poorly eliminated in urine and faeces.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic radiopharmaceuticals, hepatic and reticulo endothelial system, technetium ( ^9mTc) nanocolloid, ATC Code: V09DB01.

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

At least 95% of the colloidal particles which form Nanocoll have a diameter <80 nm, a size range considered adequate for lymphoscintigraphy applications.

Sentinel Lymph Node Imaging

The sentinel node is defined as the first lymph node of the lymphatic basin to receive drainage from a determined region. The latter virtually always corresponds to the first tumoral implantation site, since dissemination typically occurs in an orderly and sequential way. Nevertheless, sentinel node analysis can assist in defining the status of the entire lymphatic basin.

Following reconstitution and labelling, Nanocoll is intended to be injected in close proximity to the tumour and used in preoperative imaging and/or intraoperatively in conjunction with a gamma detection probe to localise sentinel lymph nodes in the lymphatic pathway draining the tumour. In published studies Nanocoll has demonstrated an acceptable level of efficacy in sentinel lymph node identification.

5.2 Pharmacokinetic properties

Distribution

After intravenous injection, 99mTc-nanocolloid is rapidly cleared from plasma and taken up by the reticuloendothelial system. About 15- 20% is accumulated in the bone marrow by macrophages, the rest being distributed to the liver (70%) and spleen (10%).

Following subcutaneous administration, approximately 30-40% of the colloidal particles of ^99mTc-labelled albumin are filtered in the lymphatic capillaries, which have the principle function of draining proteins from the interstitial fluid and returning them to the blood. From here the particles are transported through the lymphatic vessels into the local lymph nodes and main lymphatic vessels, and are finally trapped in the reticular cells of the main lymph nodes.

A fraction of the injected dose is phagocytosed by the histiocytes at the injection site. A fraction of the injected dose is transported in the blood and accumulates mainly in the reticuloendothelial system (RES) of the liver, spleen and bone marrow, minimal traces are eliminated through the kidneys. The maximum concentration in the liver and spleen is reached after about 30 minutes, but in the bone marrow after only 6 minutes.

Organ uptake

The subcutaneous administration of the nanocolloid is followed by a rapid and massive lymphatic drainage that makes it possible to trace the flow in the lymphatic vessels by means of dynamic scanning, for at least 30 minutes. It is then possible to run a total body scan or a Single photon emission computed tomography (SPECT). With regard to the lymph nodes proximal to the injection site, it is possible to visualise them after 5 minutes from administration.

Elimination

The metabolic degradation of Nanocoll is slow, and the half life in the body is about 32 hours, bearing witness to its stability in-vivo. Its elimination occurs through the kidneys and to a lesser extent through the gastrointestinal system. The rate of excretion is not influenced by administration of other pharmaceuticals, thus ensuring for the patient the possibility of continuing any ongoing therapies at the time of the examination.

The metabolic degradation has a relatively low coefficient (1.5% per hour). This constitutes a safe technical advantage, even in the case of late scans made possible by the good in-vivo stability. However, this is associated with a relative disadvantage represented by the larger radiation dose in the fixation sites.

A fraction of the injected dose is phagocytized by histiocytes at the injection site. Another fraction appears in the blood and accumulates mainly in the 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 subcutaneously injected with 1g/kg.

These doses correspond to the contents of several tens of vials per kg body weight, compared to the human albumin colloid dose of 7 micrograms /kg generally used in nuclear medicine for diagnosis.

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

6.1. List of excipients

Stannous chloride, dihydrate Glucose, anhydrous Poloxamer 238

Sodium phosphate, dibasic, anhydrous Sodium phytate, anhydrous

6.2. Incompatibilities

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

6.3 Shelf life

1 year (12 months) from the date of manufacture.

The reconstituted product should be stored below 25°C. Do not refrigerate or freeze. It should be used within 6 hours after labelling.

6.4 Special precautions for storage

Store in a refrigerator (2°C to 8°C).

For storage conditions of the reconstituted product, see section 6.3.

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

6.5. Nature and contents of container

10 ml, Type I Ph.Eur., glass vials sealed by bromobutyl rubber stoppers and metal flip off caps.

Pack size: kit contains 5 vials

6.6 Special precautions for disposal and other handling

Radiopharmaceuticals should be received, used and administered only by authorized persons in designated clinical settings. Its receipt, storage, use, transfer and disposal are subject to the regulation and/or appropriate licenses of local competent official organisations.

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

Contents of the vial are intended only for use in the preparation of 99m Tc-human albumin nanocolloid and are not to be administered directly to the patient without first undergoing the preparative procedure

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

The content of the kit before reconstitution is not radioactive. However, after Sodium Pertechnetate (^99mTc) Injection 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 spills of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken.

Normal safety precautions for handling radioactive materials should be observed. After use, all materials associated with the preparation and administration of radiopharmaceuticals, including any unused product and its container, should be decontaminated or treated as radioactive waste and disposed of in accordance with the conditions specified by the local competent authority. Contaminated material must be disposed of as radioactive waste via an authorised route.

7. Marketing Authorization Holder

GE Healthcare S.r.l.

Via Galeno, 36 20126 - Milan - Italy

PL 16991/0001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 June 1998

Date of the last renewal: 09 May 2002

10    DATE OF REVISION OF THE TEXT

28/09/2015

11    DOSIMETRY

99m    99    99m

Technetium ( Tc) is produced by means of a ( Mo/ Tc) generator and decays with the emission of gamma radiation with a mean energy of 140 keV and a half-life

99    5

of 6.02 hours to technetium ( Tc) which, in view of its long half-life of 2.13 x 10 years can be regarded as quasi stable.

The radiation dose estimation for a number of organs is based on MIRD reference man and MIRD S values, and has been calculated from biological data of organ uptake and blood clearance.

The radiation doses absorbed by a patient weighing 70 kg, after intravenous injection of

technetium-99m human albumin colloidal particles, are reported hereafter.

Organ	Absorbed dose (p,Gy/MBq)
Liver	78
Urinary bladder (wall)	25
Spleen	18
Bone marrow (red)	14
Ovaries	3.2
Testes	1.1
Whole body	5.1

For this product the effective dose resulting of an administered activity of 500 MBq is

2.5 mSv (per 70 kg individual).

For an administered activity of 500 MBq the typical radiation dose to the critical organ (liver) is 39 mGy and the typical radiation dose to the target organ (red bone marrow) is 7.0 mGy.

The radiation doses absorbed by a patient weighing 70 kg, after subcutaneous injection of technetium-99m human albumin colloidal particles, are reported hereafter.

Organ	Absorbed dose (pGy/MBq)
Injection site	12,000
Lymph nodes	590
Liver	16
Urinary bladder (wall)	9.7
Spleen	4.1
Bone marrow (red)	5.7
Ovaries	5.9
Testes	3.5
Whole body	4.6

For this product the effective dose equivalent resulting of an administered activity of 110 MBq is 0.44 mSv (per 70 kg individual).

For an administered activity of 110 MBq the typical radiation dose to the target organ (lymph nodes) is 65 mGy and to the critical organ (injection site) 1320 mGy.

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

Method of preparation

-    Place a vial containing the albumin colloidal particles in a convenient lead shield.

-    Aseptically introduce into the vial 1-5 ml Sodium Pertechnetate (^99mTc) Injection Ph. Eur. with a radioactivity ranging from 185 to 5550 MBq (5 to 150 mCi).

-    In children, it is possible to dilute the product up to 1:50 with sodium chloride for injection.

-    Do not use a breather needle.

-    Relieve the excess of pressure in the vial by simply withdrawing an equal volume of gas in the syringe.

-    Invert carefully a few times to dissolve the contents of the vial.

-    For paper chromatography allow to stand for 5-10 minutes at room temperature (15°C -25°C).

-    For chromatography on TLC-SA allow to stand for 30 minutes at room temperature (15°C -25°C).

-    Shake before withdrawing a dose.

-    In no case should the preparation be left in contact with air.

The disposal of waste should be in accordance with national and international guidelines.

Quality control

RCP by ascending paper chromatography:

Support: paper Whatman No. 1 Solvent: methanol: water 85 : 15 v/v Time: 1 hour

^99mTc (nanocolloid): > 95%

Rf [^99mTc (nanocolloid)]: 0.0%

Free 99m-Tc pertechnetate migrate with Rf 0.7 + 10%

B - RCP by ascending chromatography on TLC-SA:

Support: TLC-SA (2 x 12 cm strips; dispose a small drop of preparation at 2.5 cm of the bottom)

Solvent : methanol: water 85 : 15 v/v

Time: 25-30 minutes (approximately at 7 cm from the origin; remove strip from the tank and allow it to dry)

^99mTc (nanocolloid): > 95%

Rf [^99mTc (nanocolloid)]: 0.0 - 0.1

Free 99m-Tc pertechnetate and other Technetium-hydrophilic complexes migrate with Rf 0.8 - 1.0

Do not use material if the radiochemical purity is less than 95%