This information is intended for use by health professionals

  This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Lymphoseek 50 micrograms kit for radiopharmaceutical preparation

2. Qualitative and quantitative composition

Each vial contains 50 micrograms of tilmanocept. An additional overfill is included in each vial to ensure that 50 micrograms of tilmanocept can be delivered.

The radionuclide is not part of the kit.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Kit for radiopharmaceutical preparation.

The vial contains a sterile, non-pyrogenic, white to off-white lyophilized powder.

4. Clinical particulars
4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

Radiolabelled Lymphoseek is indicated for imaging and intraoperative detection of sentinel lymph nodes draining a primary tumour in adult patients with breast cancer, melanoma, or localised squamous cell carcinoma of the oral cavity.

External imaging and intraoperative evaluation may be performed using a gamma detection device.

4.2 Posology and method of administration

This medicinal product is restricted to hospital use only.

The medicinal product should only be administered by trained healthcare professionals with technical expertise in performing and interpreting sentinel lymph node mapping procedures.

Posology

The recommended dose is 50 micrograms tilmanocept radiolabelled with technetium Tc 99m at 18.5 MBq for same day surgery or 74 MBq for next day surgery. The dose of 50 micrograms should not be adjusted for body weight differences. The total injection amount should not exceed 50 micrograms tilmanocept, with a total maximum radioactivity of 74 MBq (2.0 mCi) per dose.

The recommended minimum time for imaging is 15 minutes post injection. Intraoperative lymphatic mapping may begin as early as 15 minutes post injection.

Patients scheduled for surgery on the day of injection will receive 18.5 MBq technetium Tc 99m labelled product. Administration should occur within 15 hours of the scheduled time of the surgery and intraoperative detection.

Patients scheduled for surgery on the day after injection will receive 74 MBq technetium Tc 99m labelled product. Administration should occur within 30 hours of the scheduled time of the surgery and intraoperative detection.

Patients with hepatic or renal impairment

Careful consideration of the activity to be administered in these patients is required since an increased radiation exposure is possible. The radiation dose to the patient would not exceed 0.69 mSv even if none of a 74 MBq dose were eliminated.

Extensive dose-range and adjustment studies with the medicinal product in normal and special populations have not been performed. The pharmacokinetics of technetium Tc 99m tilmanocept in patients with renal or hepatic impairment have not been characterised (see section 5.2).

Elderly population

Elderly patients aged 65 or older (32%) were evaluated in clinical studies; no safety issues were identified. No dose adjustment is recommended based on age.

Paediatric population

The safety and efficacy of Lymphoseek in children and adolescents below the age of 18 years has not yet been established. No data are available.

Method of administration

This medicinal product must be radiolabelled before administration to the patient. The radiolabelled product is a clear, colourless solution with no visible particles.

Following radiolabelling, administration can be by either intradermal, subcutaneous, intratumoural, or peritumoural injection.

For melanoma, administration is intradermal in single or multiple divided injections.

For breast cancer, administration is intradermal, subareolar (single or multiple divided injections) or peritumoural (multiple divided injections).

For squamous cell carcinoma of the oral cavity, administration is peritumoural (multiple divided injections).

Each 50 microgram vial contains an additional overfill to ensure that 50 micrograms of tilmanocept can be delivered. However, it is required that the vial be prepared as instructed and a 50 microgram aliquot be used for a single patient dose.

Individual injection volumes should not exceed 0.5 mL or be less than 0.1 mL. Total injection volume should be no greater than 1.0 mL and no less than 0.1 mL. Dilution of the product in volumes greater than 1.0 mL could affect the in vivo disposition of Lymphoseek.

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

For patient preparation, see section 4.4.

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or to any of the components of the radiolabelled pharmaceutical.

4.4 Special warnings and precautions for use

Potential for hypersensitivity or anaphylactic reactions

The possibility of hypersensitivity including severe life-threatening fatal anaphylactic / anaphylactoid reactions must 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.

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.

Renal and hepatic impairment

Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is possible. The estimated radiation dose to the patient would not exceed 0.69 mSv even if none of a 74 MBq dose (2.0 mCi) were eliminated (see section 4.2).

Patient preparation

The patient should be well hydrated before the start of the examination and frequent voiding of urine during the initial hours after examination would reduce radiation exposure to the patient.

Specific warnings

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

Precautions with respect to environmental hazard see section 6.6.

4.5 Interaction with other medicinal products and other forms of interaction

Adding very large volumes of tracing agents or other injectants temporally or anatomically proximal to Lymphoseek could affect the in vivo disposition of Lymphoseek. Additional tracing agents should not be injected within 30 minutes of Lymphoseek administration.

No other interaction studies have been performed.

4.6 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

There are no data from the use of Lymphoseek in pregnant women. No reproductive toxicity studies in animals were performed, and it is not known if Lymphoseek can cause foetal harm when administered to a pregnant woman.

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.

Breast-feeding

It is not known whether technetium Tc 99m tilmanocept is excreted into human milk.

Before administering radiopharmaceuticals to a mother who is breast-feeding consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breast-feeding, and to what is the most appropriate choice of radiopharmaceuticals, bearing in mind the secretion of activity in breast milk. If administration is considered necessary, breast-feeding should be interrupted for 24 hours post injection and the expressed feeds discarded.

Fertility

Animal fertility studies have not been conducted with Lymphoseek.

4.7 Effects on ability to drive and use machines

Lymphoseek has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable effects

In clinical trials with 553 patients, the most common adverse reactions were:

◦ Injection site irritation (0.7%; 4 of 553 patients)

◦ Injection site pain (0.2%; 1 of 553 patients)

Other adverse reactions were uncommon, and of mild severity and short duration.

The following table presents how the frequencies are reflected in this section:

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 from the available data)

Clinical studies have evaluated the incidence of adverse reactions listed below in 553 subjects 18 years and above who received Lymphoseek. These reactions were temporally related to Lymphoseek administration and could be due to other medicinal products administered to patients or surgical procedures.

Metabolism and nutrition disorders

Uncommon: Hypercalcaemia

Nervous system disorders

Uncommon: Aphasia, Dizziness, Headache, Paraesthesia

Eye disorders

Uncommon: Vision blurred

Cardiac disorders

Uncommon: Sinus tachycardia

Vascular disorders

Uncommon: Flushing

Gastrointestinal disorders

Uncommon: Nausea

Skin and subcutaneous tissue disorders

Uncommon: Skin irritation

Musculoskeletal and connective tissue disorders

Uncommon: Pain in extremity, Musculoskeletal pain, Neck pain, Pain in jaw

Renal and urinary disorders

Uncommon: Micturition urgency, Pollakiuria

Reproductive system and breast disorders

Uncommon: Breast pain

General disorders and administration site conditions

Uncommon: Injection site irritation, Injection site pain, Feeling hot

Injury, poisoning and procedural complications

Uncommon: Incision site pain, Seroma, Wound dehiscence

Exposure to ionizing radiation is linked with cancer induction and a potential for the development of hereditary defects. As the effective dose to an adult (70 kg) is 0.69 mSv when the maximal recommended activity of 74 MBq is administered adverse events are expected to occur with a low probability.

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 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

The total injection amount should not exceed 50 micrograms tilmanocept, with a total maximum radioactivity of 74 MBq per dose. Chronic or acute overdose is unlikely to occur given the total injection amount.

No clinical consequences were observed at dose levels of 3.7 times the recommended dose of Lymphoseek in humans, or at 390 times the anticipated human exposure of tilmanocept in animals.

In the event of administration of a radiation overdose with tilmanocept the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by frequent micturition or by forced diuresis and frequent bladder voiding

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: diagnostic radiopharmaceutical, tumour detection, ATC Code: V09IA09.

Mechanism of action

Lymphoseek is a receptor-targeted radiopharmaceutical that is designed to rapidly transit lymphatic vessels; it biotargets, accumulates, and is retained in primary, key predictive, draining lymph nodes (sentinel lymph nodes). The drug substance, tilmanocept, specifically binds to mannose binding receptor proteins (CD206) that reside on the surface of macrophages and dendritic cells. Macrophages are present in high concentrations in lymph nodes.

Tilmanocept is a macromolecule consisting of multiple units of diethylenetriaminepentaacetic acid (DTPA) and mannose, each synthetically attached to a 10 kDa dextran backbone. The mannose acts as a substrate for the receptor, and the DTPA serves as a chelating agent for labelling with technetium Tc 99m. The mean diameter of tilmanocept is 7 nm and this small molecular size permits enhanced transit into lymphatic channels resulting in rapid and consistent injection site clearance.

Following reconstitution and labelling, Lymphoseek is intended to be injected in close proximity to the tumour and used in preoperative gamma detection imaging in conjunction with a stationary gamma camera (scintigraphy), single photon emissioncomputed tomography (SPECT), or SPECT/computerized tomography SPECT/CT, and/or intraoperatively in conjunction with a gamma detection probe to localise sentinel lymph nodes in the lymphatic pathway draining the tumour.

In in vitro studies, technetium Tc 99m tilmanocept exhibited specific and tight binding to human CD206 receptors with a primary binding site affinity of Kd = 2.76 x x 10-11 M. In Phase 1 clinical studies, approximately 0.5 to 1.8% of the dose is accumulated in draining lymph nodes through specific binding after 30 minutes. Technetium Tc 99m tilmanocept binding is independent of tumour type or severity.

Clinical efficacy

In Phase 3 clinical studies, technetium Tc 99m tilmanocept was detectable in sentinel lymph nodes within 10 minutes. In external gamma imaging analysis, bound technetium Tc 99m tilmanocept has been shown to be retained in the same draining lymph nodes for up 30 hours. Preoperative lymphoscintigraphy was performed in 100% of melanoma patients, 100% of head and neck squamous cell carcinoma patients, and 82% of breast cancer patients. The overall rate of agreement between lymph node localisation (determined by radioactivity detection) on preoperative lymphoscintigraphy and intraoperative lymph node survey was 97.8% for all patients.

In Phase 3 clinical studies in breast cancer patients mapped with both technetium Tc 99m tilmanocept and vital blue dye, technetium Tc 99m tilmanocept localised in 99.91% of patients with a mean 2.08 localised sentinel lymph nodes per patient by fixed effects meta-analyses. These rates were significantly greater (p<0.0001) against a random effects meta-analysis of localisation rates from published literature for colloidal lymphatic mapping agents as used in European clinical practice. In a fixed effects meta-analysis of two Phase 3 studies, technetium Tc 99m tilmanocept localised in 99.99% of the excised lymph nodes stained blue by a vital blue dye (concordance). Alternatively, vital blue dye localised in 66.96% of the excised lymph nodes detected by technetium Tc 99m tilmanocept (reverse concordance).

In Phase 3 clinical studies in melanoma patients mapped with both technetium Tc 99m tilmanocept and vital blue dye, technetium Tc 99m tilmanocept localised in 99.89% of patients with a mean 2.30 localised sentinel lymph nodes per patient by fixed effects meta-analyses. These rates were significantly greater (p<0.0001) against a random effects meta-analysis of localisation rates from published literature for colloidal lymphatic mapping agents as used in European clinical practice. In a fixed effects meta-analysis of two Phase 3 studies, technetium Tc 99m tilmanocept localised in 99.99% of the excised lymph nodes stained blue by a vital blue dye (concordance). Alternatively, vital blue dye localised in 63.50% of the excised lymph nodes detected by technetium Tc 99m tilmanocept (reverse concordance).

In one Phase 3 clinical study in patients with intraoral or cutaneous squamous cell carcinoma, technetium Tc 99m tilmanocept localised sentinel lymph nodes in 97.59% of patients who underwent lymph node evaluation. Relative to the pathology status of lymph node collection from a complete lymph node dissection, technetium Tc 99m tilmanocept correctly localised in sentinel lymph nodes predictive of harbouring metastatic tumour in 38 of 39 patients, for a false negative rate of 2.56%. The overall accuracy of technetium Tc 99m tilmanocept for identification of true positive and true negative patients relative to pathology in the localised lymph nodes was 98.80%.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Lymphoseek in one or more subsets of the paediatric population for visualisation of lymphatic drainage of solid malignant tumours for diagnostic purposes (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Two Phase 1 clinical trials in breast cancer patients and one Phase 1 study in melanoma patients have been completed. The purpose of the studies included the radiopharmacokinetic evaluation of Lymphoseek.

Distribution

In one Phase 1 study in breast cancer patients, Lymphoseek at all three doses tested (4, 20, and 100 micrograms) exhibited fast injection site clearance (elimination rate constants in the range of 0.222/h to 0.278/h). Uptake of technetium Tc 99m tilmanocept into the primary sentinel node increased dose-dependently (p=0.009): Lymphoseek injection at 4, 20, and 100 micrograms produced primary sentinel node levels (LSN) of 0.09 ± 0.20 pmol, 6.53 ± 2.52 pmol, and 10.58 ± 8.43 pmol of technetium Tc 99m tilmanocept, respectively. The percent-of-injected dose reaching the primary sentinel node (%IDSN) was 0.05% ± 0.10%, 0.52% ± 0.38%, 0.21% ± 0.17% in the 4, 20, and 100 microgram Lymphoseek dose groups, respectively. The plasma %ID per gram for two dose levels peaked at 4 hours; the mean values for the 4 and 100 microgram doses were 0.0090%/g ± 0.0048%/g and 0.0039%/g ± 0.0046%/g, respectively. The 20 microgram dose peaked at 2.5 hours with a mean %ID/g of 0.0023%/g ± 0.0005%/g.

In the second Phase 1 study in breast cancer patients in which patients were injected with 20 micrograms Lymphoseek, the mean elimination rate constant of technetium Tc 99m tilmanocept was 0.299/h and the drug half-life at the injection site was 2.6 h. The %IDSN was 1.68% ± 1.22% in the 3 hour injection-to-surgery group and 1.81% ± 2.19% in the Lymphoseek 16 hour injection-to-surgery group.

In the Phase 1 study in melanoma patients, Lymphoseek at all three doses tested (20, 100, and 200 micrograms) cleared the injection site with elimination rate constants in the range of 0.227/h to 0.396/h, resulting in drug half-life at the injection site of 1.75 to 3.05 h). Uptake of technetium Tc 99m tilmanocept into the primary sentinel node increased dose-dependently: Lymphoseek injection at 20, 100, and 200 micrograms produced LSN values of 5.01 ± 8.02 pmol, 17.5 ± 13.7 pmol, and 58.2 ± 41.2 pmol of technetium Tc 99m tilmanocept, respectively. The %IDSN taken up into the primary lymph node was 0.50% for the 20 microgram dose, 0.35% for the 100 microgram dose, 0.58% for the 200 microgram dose of Lymphoseek. The plasma %ID per gram for two dose levels peaked at 15 minutes; the mean values for the 20 and 200 microgram doses were 0.0104%/g ± 0.0135%/g and 0.0065%/g ± 0.0082%/g, respectively. The 100 microgram dose peaked at 1 and 2 hours with a mean %ID/g of 0.0018%/g ± 0.001%/g at each timepoint.

Elimination

Technetium Tc 99m tilmanocept is eliminated primarily through the kidneys. The metabolism of technetium Tc 99m tilmanocept has not been investigated experimentally. Tilmanocept may be metabolised in the liver to its component molecules, namely dextran (which is renally excreted and/or further metabolised to glucose), mannose (an endogenous sugar) and diethylenetriaminepentaacetic acid (which is renally excreted). As with all general metabolites, especially those in which the liver plays a measurable roll of elimination, some biliary elimination of technetium Tc 99m tilmanocept is also likely to occur.

The %ID for liver, kidneys, and bladder as calculated from the whole body scans of breast cancer patients at 1, 2.5, and 12 hours after administration was below 2.6% at all times (all dose levels combined). The %ID for liver, kidneys, and bladder as calculated from the whole body scans of melanoma patients at 1 and 12 hours after administration ranged from 1.1% to 3.1% at 1 hour, and all decreased to less than 1% by 12 hours.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity, and genotoxicity.

6. Pharmaceutical particulars
6.1 List of excipients

Trehalose, dihydrate

Glycine (E640)

Sodium ascorbate (E301)

Stannous chloride, dihydrate (E512)

Sodium hydroxide (E524)

Hydrochloric acid, dilute (E507)

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

18 months.

After radiolabelling

6 hours. Do not store above 25°C. Store using appropriate radiation shielding.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Do not store above 25°C.

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

For storage conditions after radiolabelling of the medicinal 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

8 mL type I glass vial with a butyl rubber stopper sealed with a flip-off seal. Each vial contains 50 micrograms tilmanocept.

Pack-size of 1 and 5 vials.

6.6 Special precautions for disposal and other handling

General warning

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 licenses of the competent official organisation.

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 and radiolabelling of Lymphoseek and are not to be administered directly to the patient without first undergoing the preparative procedure. Each 50 microgram vial contains an additional overfill to ensure that 50 micrograms of tilmanocept can be delivered. However, it is required that the vial be prepared as instructed and a 50 microgram aliquot be used for a single patient dose; any remaining material should be discarded after reconstitution and use, see section 12.

For instructions on reconstitution and radiolabelling of the medicinal product before administration, see section 12. The radiolabelled product is a clear, colourless solution with no visible particles.

If at any time in the preparation of this product the integrity of this vial is compromised it should not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

The content of the kit before extemporary preparation is not radioactive. However, after sodium pertechnetate (99mTc), 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 spill of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken.

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

7. Marketing authorisation holder

Norgine B.V.

Antonio Vivaldistraat 150

1083 HP Amsterdam

Netherlands

8. Marketing authorisation number(s)

EU/1/14/955/002

EU/1/14/955/001

9. Date of first authorisation/renewal of the authorisation

19 November 2014

10. Date of revision of the text

Nov 2018

DOSIMETRY

Technetium (99mTc) is produced by means of a (99Mo/99mTc) generator and decays with the emission of gamma radiation with a mean energy of 140 keV and a half-life of 6.02 hours to technetium (99mTc) which, in view of its long half-life of 2.13 x 105 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 to organs and tissues of an average patient (70 kg) per MBq of radiolabelled Lymphoseek are shown in Table 1 and Table 2.

Table 1. Estimated dose absorbed from Lymphoseek in patients with breast cancera

Estimated radiation absorbed dose for breast cancer, mGy/MBq

Target organ

Adults

brain

0.0002

breast (injection site)

0.0897

gall bladder wall

0.0019

lower large intestine wall

0.0007

small intestine

0.0005

stomach

0.0010

upper large intestine wall

0.0007

kidney

0.0101

liver

0.0018

lungs

0.0020

muscle

0.0005

ovaries

0.0101

red marrow

0.0007

bone

0.0010

spleen

0.0015

testes

0.0027

thymus

0.0063

thyroid

0.0048

urinary bladder

0.0032

total body (blood)b

0.0011

Effective dose (E)

(males, mSv/MBq)

0.01600

Effective dose (E)

(females, mSv/MBq)

0.01785

a Calculated from data of 18 breast cancer patients who received four peritumoural injections of 4, 20, and 100 microgram doses of Lymphoseek.

b Blood represents total body exposure segregated from independent measurements of other organs and tissues.

Table 2. Estimated dose absorbed from Lymphoseek in patients with melanomaa

Estimated radiation absorbed dose for melanoma, mGy/MBq

Target organ

Adults with melanoma

brain

0.0050

breast (injection site)

0.0427

gall bladder wall

0.0038

lower large intestine wall

0.0031

small intestine

0.0032

stomach

0.0030

upper large intestine wall

0.0031

kidney

0.0150

liver

0.0050

lungs

0.0032

muscle

0.0024

ovaries

0.0162

red marrow

0.0027

bone

0.0047

spleen

0.0032

testes

0.0056

thymus

0.0031

thyroid

0.0025

urinary bladder

0.0076

total body (blood)b

0.0030

Effective dose (E)

(males, mSv/MBq)

0.01094

Effective dose (E)

(females, mSv/MBq)

0.01357

a Calculated from data of 18 melanoma patients who received four intradermal injections of 20, 100, and 200 microgram doses of Lymphoseek.

b Blood represents total body exposure segregated from independent measurements of other organs and tissues.

INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

Radiation safety – Product handling

Use waterproof gloves, effective radiation shielding, and appropriate safety measures when handling Lymphoseek to avoid unnecessary radiation exposure to the patient, occupational workers, clinical personnel, and other persons.

Radiopharmaceuticals should be used by or under the control of healthcare professionals who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorised to license the use of radionuclides.

Directions for radiolabelling the tilmanocept powder 50 micrograms vial with technetium Tc 99m general considerations

The vial components of the kit are sterile, non-pyrogenic, and are intended solely for use in the preparation of Lymphoseek. Do not administer the unprepared vial components of the kit directly to a patient.

Follow aseptic procedures during preparation and administration.

Follow appropriate radiation safety precautions during preparation and administration. Use radiation shielding for radiolabelled Lymphoseek to prevent radiation exposure.

Use only eluate from technetium Tc 99m generator which was previously eluted within 8 hours. For the highest radiochemical purity, reconstitute with freshly eluted technetium Tc 99m generator eluate.

Technetium Tc 99m labelling reactions depend on maintaining the stannous ion in the reduced state. Sodium pertechnetate (Tc 99m) injection containing oxidants should not be used to reconstitute this kit. Vials are sealed under nitrogen; air or oxygen is harmful to the contents of the vial and therefore the vial should not be vented.

Lymphoseek, radiolabelled solution for injection should be used within 6 hours after reconstitution. The dose must contain no less than the intended level of Tc 99m radioactivity for same day surgery (18.5 MBq) or next day surgery (74 MBq) at the time of administration.

Determination of injection volumes

Lymphoseek may be administered to a patient as a single injection or as multiple injections. Prior to preparation, determine the planned injection technique and the number of injections that will be used for a given patient. For each injection prepare a separate syringe. Based on the planned number of injection syringes and the planned total injection volume per patient, determine (from Table 3 below) the reconstituted vial volume of radiolabelled Lymphoseek.

Each Lymphoseek vial, once reconstituted and radiolabelled, would contain 50 micrograms of product with an additional overfill when prepared according to the instructions and administered as noted in Table 3. The overfill is 12.5 micrograms to allow for radiochemical purity testing and to ensure that 50 micrograms of tilmanocept can be delivered. The total contents of the vial should not be administered to a single patient. The radiolabelled product is to be used within 6 hours of its preparation. Discard unused product.

Table 3: Lymphoseek injections by injection volume

Desired number of injections

Total volume to be injected

Total Lymphoseek vial reconstitution volume

1 x 0.1 mL injection

0.1 mL

0.125 mL

5 x 0.1 mL injections, or

2 x 0.25 mL injections, or

1 x 0.5 mL injection

0.5 mL

0.625 mL

5 x 0.2 mL injections, or

4 x 0.25 mL injections, or

2 x 0.5 mL injections

1.0 mL

1.25 mL

Method of preparation

Preparation of the Lymphoseek radiolabelled solution for injection from the kit is done by the following aseptic procedure:

a. Prior to radiolabelling, inspect the tilmanocept powder vial for any damage. Do not use if vial integrity appears compromised.

b. For radiolabelling, use sodium pertechnetate (Tc 99m) solution from a technetium Tc 99m generator within 8 hours of its elution.

c. Do not vent the tilmanocept powder vial prior to or during radiolabelling.

d. Using a sterile syringe, aseptically draw approximately 23.1 MBq or 92.5 MBq of sodium pertechnetate (Tc 99m) solution in either about 0.125 mL volume (for 0.125 mL reconstituted vial volume) or about 0.5 mL volume (for 0.625 mL or 1.25 mL reconstituted vial volume). Assay the syringe for technetium Tc 99m activity in a dose calibrator.

e. Prior to radiolabelling, write the radioactivity amount, the reconstituted vial volume, date and time, expiration time and lot number in the space provided on the radioactive product vial label and affix it to the tilmanocept powder vial. Place the vial in a radiation shield and sanitize the septum with an alcohol wipe.

f. Aseptically add sodium pertechnetate (Tc 99m) solution (from step d above) to the tilmanocept powder vial. Without withdrawing the needle, remove an equal volume of headspace gas. Do not vent.

g. Remove the needle, gently swirl the vial to mix the contents, and then let it stand at room temperature for at least 15 minutes.

h. Aseptically add sterile sodium chloride 9 mg/mL (0.9%) solution for injection, if needed, to the radiolabelled product in the tilmanocept powder vial to bring the volume to the reconstituted vial volume of 0.125 mL, 0.625 mL, or 1.25 mL prior to filling the patient dose in syringe(s). To normalize pressure, withdraw an equal volume of headspace gas.

i. Assay the radiolabelled vial for total radioactivity using a dose calibrator. Write the technetium Tc 99m activity concentration, total volume, assay time and date, expiration time, and lot number on the shield label supplied with the kit. Affix the label to the shield.

j. Determine the radiochemical purity of the radiolabelled product as described below.

k. Withdraw the required volume of the radiolabelled product into the required number of syringes. Assay the syringe(s) in a dose calibrator. Write the radioactivity amount, date and time of assay, volume, and expiration time (this is not to exceed 6 hours from preparation time) on a syringe label and affix it to the syringe(s).

l. Store the radiolabelled product in a shield. Do not store above 25°C. Use within the expiry time on the label.

Determination of radiochemical purity of radiolabelled Lymphoseek

Determine radiochemical purity of the radiolabelled Lymphoseek by Instant Thin Layer Chromatography (ITLC) using either Whatman Grade 1, 3MM, 31ET Chr or Biodex 150-001 Red Strips (cellulose chromatography paper) using the following method:

a. Mark the chromatographic strip for origin, mid and solvent front lines with a pencil as shown below:

b. Apply a small drop (3 - 10 microliters) of the radiolabelled product at the center of the origin line chromatography strip.

c. Place the strip into a chromatography chamber containing 1 mL of acetone as the developing solvent. Allow the solvent to migrate to the solvent front line (5 cm from the bottom of the Whatman strips and 3.5 cm for the Biodex strip). Remove the strip from the chamber, let it dry and cut it in half. Count each half of the strip with a suitable radioactivity counting apparatus (dose calibrator or multichannel analyzer).

d. Calculate the percent radiochemical purity (% RCP) as follows:

e. Do not use the radiolabelled Lymphoseek if the radiochemical purity is less than 90%.

Image acquisition/sentinel lymph node mapping

Breast cancer, melanoma, and squamous cell carcinoma of the oral cavity applications in adults:

• In clinical studies, patients received Lymphoseek up to 30 hours before surgery. A handheld gamma counter (represented by any handheld gamma detection probe) was used intraoperatively to identify sentinel lymph nodes localising technetium Tc 99m. In clinical studies using Lymphoseek, study investigators employed a threshold rule for positive localisation of technetium Tc 99m that was estimated using the background radioactivity counts plus three standard deviations from the mean background count level (i.e., the three-sigma rule, representing >99.7% probable difference from background) [see Table 4]. Background counts were typically determined from tissue at least 20 centimetres distal to the injection site.

Table 4: Example of three-sigma rule threshold

Background counta

Three-sigma threshold value

5

11.71

10

19.49

15

26.62

20

33.42

25

40.00

a Average of three 2-second counts or one 10-second count

• All lymphatic mapping agents use elements of the lymphatic system for distribution. The imaging and detection of sentinel lymph nodes with Lymphoseek is dependent upon its specific molecular targeting and binding to reticuloendothelial cells within lymph nodes. Distortion of the underlying lymphatic system architecture and function by prior extensive surgery, radiation, or metastatic disease may result in diminished Lymphoseek localisation in lymph nodes. Based on clinical studies, the rate of localisation (percent of all patients with at least one hot node) and degree of localisation (average number of hot nodes per patient) of Lymphoseek is not dependent on the radiopharmaceutical injection technique. The use of Lymphoseek is intended to complement palpation, visual inspection, and other procedures important to lymph node localisation. Intraoperative lymphatic mapping by gamma detection may begin as early as 15 minutes post-injection and within 30 hours (for next day surgery) of administration of Lymphoseek.

• After injection of Lymphoseek, external gamma detection imaging may be conducted. Recommended time for preoperative imaging is 15 minutes post-injection but may begin as early as 10 minutes. Effective preoperative imaging procedures include planar gamma camera scintigraphy, SPECT, and SPECT/CT. Although these are complementary to intraoperative gamma probing, such acquired images should not be considered a substitute for proficient and thorough intraoperative probing with a handheld gamma detection probe.

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.