Lymphoseek - summary of medicine characteristics

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.

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 PARTICULARS4.1 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 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 radiolabelled 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 radiolabelled product. Administration should occur within 30 hours of the scheduled time of the surgery and intraoperative detection.

Special populations

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 2.28 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 product.

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 2.28 mSv even if none of a 74 MBq dose 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, that is to say essentially ‘sodium-free’.

For 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 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 and use machines.

4.8 Undesirable effects

Summary of safety profile

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.

Tabulated list of adverse reactions

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.

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories 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 (frequency cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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 1.32 mSv when the maximal recommended activity of 74 MBq is administered adverse reactions 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 the national reporting system listed in Appendix V.

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 PROPERTIES5.1 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 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 PARTICULARS6.1 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

Unopened vial 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 medicinal 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) 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

Navidea Biopharmaceuticals Europe Ltd.

Kilminion South

Ballinroad

Dungarvan

Co. Waterford, X35 WP70

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/955/002

EU/1/14/955/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 November 2014

Date of latest renewal: 16 September 2019