2.1 Radiation Safety – Drug Handling

Lymphoseek is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure.[see Warnings and Precautions (5.2)]  Use waterproof gloves, effective radiation shielding, and appropriate safety measures when preparing and handling Lymphoseek. 

Radiopharmaceuticals should be used by or under the control of physicians 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 authorized to license the use of radionuclides.

2.2 Recommended Dose

The recommended dose of  Lymphoseek is 18.5 MBq (0.5 mCi) as a radioactivity dose and 50 mcg as a mass dose, administered at least 15 minutes prior to initiating intraoperative lymphatic mapping.  The recommended total injection volume for each patient (Table 1) is 0.1 mL administered in a single syringe; 0.5 mL administered in a single syringe or in multiple syringes (0.1 mL to 0.25 mL each); or 1 mL administered in multiple syringes (0.2 mL to 0.5 mL each).

2.3 Drug Preparation and Administration

General Considerations:

• Kit for the preparation of Lymphoseek contains five sets of two vials: a Tilmanocept Powder vial and a DILUENT for Lymphoseek vial.
  • Tilmanocept Powder vial contains 250 mcg of tilmanocept from which 50 mcg is intended for administration to a patient.
  • The DILUENT for Lymphoseek vial contains 4.5 mL of sterile buffered saline. It is used to dilute Lymphoseek after the radiolabeling procedure. The amount of diluent used varies, depending on the total injection volume and the number of syringes used for each patient.
• The vial components of the Kit for the preparation of Lymphoseek are sterile, non-pyrogenic, and are intended solely for use in the preparation of Lymphoseek (technetium Tc 99m tilmanocept) Injection. 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 radiolabeled Lymphoseek to prevent radiation exposure.

Drug Preparation Instructions:

Lymphoseek may be administered to a patient as a single injection or as multiple injections. Prior to preparation of Lymphoseek, 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 1 below) the Reconstituted Vial Volume of radiolabeled Lymphoseek.

Each Lymphoseek vial, once reconstituted and radiolabeled, would contain sufficient amount to provide doses for up to four patients when prepared according to the instructions. The radiolabeled Lymphoseek is to be used within 6 hours of its preparation. Discard the unused radiolabeled Lymphoseek.

Once the Reconstituted Vial Volume is established, use the following steps to prepare radiolabeled Lymphoseek:

1. Prior to radiolabeling, inspect the Tilmanocept Powder vial for any damage. Do not use if vial integrity appears compromised.
2. For radiolabeling, use Technetium Tc 99m pertechnetate, sodium injection solution from a technetium Tc 99m generator within 8 hours of its elution.
3. Do not vent the Tilmanocept Powder vial prior to or during radiolabeling.
4. Using a sterile syringe, aseptically draw approximately 92.5 MBq (2.5 mCi) of Technetium Tc 99m pertechnetate sodium injection solution in either about 0.35 mL volume (for 0.5 mL Reconstituted Vial Volume) or about 0.7 mL volume (for 2.5 mL or 5 mL Reconstituted Vial Volume). Assay the syringe for technetium Tc 99m activity in a dose calibrator.
5. Prior to reconstitution, 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 alcohol wipe.
6. Aseptically add Technetium Tc 99m pertechnetate, sodium injection solution (from step d above) to the Tilmanocept Powder vial. Without withdrawing the needle, remove an equal volume of headspace gas. Do not vent.
7. Remove the needle, gently shake the vial to mix the contents, and then let it stand at room temperature for at least 15 minutes.
8. Aseptically add the supplied DILUENT for Lymphoseek to the radiolabeled product in the Tilmanocept Powder vial to bring the volume to the Reconstituted Vial Volume of 0.5 mL, 2.5 mL, or 5 mL prior to filling the patient dose in syringe(s). To normalize pressure, withdraw an equal volume of headspace gas.
9. Assay the reconstituted 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.
10. Determine the radiochemical purity of the reconstituted product as described in 2.4. Do not use if the radiochemical purity is less than 90%.
11. Withdraw the required volume of the reconstituted 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 the supplied syringe label and affix it to the syringe(s).
12. Store the reconstituted product at room temperature in a shield. Use within the expiry time on the label.

Route of Administration and Injection Method:

The route of administration depends on the type of cancer and the planned injection technique. Inject Lymphoseek into a patient at least 15 minutes prior to intraoperative lymphatic mapping; do not delay mapping more than 15 hours after Lymphoseek injection. Table 2 shows the route of administration options.

2.4 Determination of Radiochemical Purity of Radiolabeled Lymphoseek

Determine radiochemical purity of the reconstituted radiolabeled 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:

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

   

2. Apply a small drop (3 - 10 microliters) of the reconstituted  product at the center of the origin line chromatography strip.  Let the product spot dry.
3. 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).
4. Calculate the percent radiochemical purity (RCP) as follows:
   
   % RCP =                   Counts bottom half                 x 100
                      Counts bottom half + Counts top half
5. Do not use the reconstituted Lymphoseek if the radiochemical purity is less than 90%. 

2.5 Lymphatic Mapping Procedures Following Injection of Lymphoseek

• Lymphoscintigraphy may be considered to help plan the lymph node mapping procedures. In clinical studies, preoperative lymphoscintigraphy was performed in most patients; the extent to which lymphoscintigraphy contributed to the success of the mapping procedures was not established. [see Clinical Studies (14)]
• Use a hand-held gamma counter to identify nodes that concentrated the injected radioactivity.
• For intraoperative lymphatic mapping, first measure the background radioactivity counts from tissue at least 20 centimeters distal to the injection site. Use the three sigma threshold (background radioactivity counts plus three times the square root of the mean background count) as an estimate of the threshold for positive localization of Lymphoseek, as exemplified in Table 3.

• Lymphoseek is intended to supplement palpation, visual inspection, and other procedures important to lymph node localization.  Intraoperative lymphatic mapping by gamma detection of Lymphoseek within lymph nodes should be initiated no sooner than 15 minutes following injection of the final product.  In clinical studies, patients also received a concomitant blue dye tracer to enhance the ability to detect lymph nodes.  While most lymph nodes were detected with Lymphoseek, some were detected only with the blue dye tracer or only with palpation. [see Clinical Studies (14)]
• The lymphatic system architecture and function may be changed by prior surgery, radiation, edema, inflammation or metastatic disease, and may result in changes to lymph node localization by a radiopharmaceutical or other tracers, including colorimetric agents.  Avoid injections into biopsy wound areas that show evidence of edema or inflammation.

2.6 Radiation Dosimetry

The radiation doses to organs and tissues of an average patient (70 kg) per 18.5 MBq (0.5 mCi) of Lymphoseek are shown in Table 4 and Table 5.

The Effective Dose Equivalents for other technetium Tc 99m-based evaluations are: 1) bone scan = 4,000 microSv; 2) thyroid scan = 1,000 microSv; and 3) lung scan = 1,000 microSv.

5.1 Hypersensitivity Reactions

Lymphoseek may pose a risk of hypersensitivity reactions due to its chemical similarity to dextran.  [see Description (11)]  Serious hypersensitivity reactions have been associated with dextran and modified forms of dextran (such as iron dextran drugs).  In clinical trials, no serious hypersensitivity reactions were reported. 

Before administering Lymphoseek, ask patients about prior reactions to drugs, especially to dextran and modified forms of dextran.  Have resuscitation equipment and trained personnel immediately available at the time of Lymphoseek administration.

5.2 Radiation Risks

Any radiation-emitting product may increase the risk for cancer, especially in pediatric patients.  Adhere to the dose recommendations and ensure safe handling to minimize the risk for excessive radiation exposure to either the patient or health care workers.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 542 patients received Lymphoseek.  No patients experienced serious adverse reactions. 

Injection site irritation (3 of 542 patients; 0.6%) and pain (1 of 542 patients; 0.2%) were reported.  Other adverse reactions were uncommon, of mild severity and short duration.

8.1 Pregnancy

Pregnancy Category C:  There are no adequate or well-controlled studies of Lymphoseek in pregnant women.

Unbound technetium crosses the placenta.  All radiopharmaceuticals, including Lymphoseek, have a potential to cause fetal harm.  The likelihood of fetal harm depends on the stage of fetal development and the radiopharmaceutical dose.  No reproduction and developmental studies have been conducted with Lymphoseek.  Lymphoseek should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether Lymphoseek is excreted in human milk.  Based on the clearance of the drug, advise patients to express and discard milk for at least four hours after administration of Lymphoseek.

Exercise caution when administering Lymphoseek to a nursing mother.

8.4 Pediatric Use

Safety and effectiveness of Lymphoseek in pediatric patients have not been established.

8.5 Geriatric Use

Of the 468 patients enrolled in breast cancer and melanoma clinical studies, 136 patients were aged 65 or older.  Review of the clinical data, including evaluation of the frequency of adverse reactions, has not identified differences in safety or efficacy between elderly patients (65 to 90 years of age) and younger patients (18 to 65 years of age).

8.6 Females of Reproductive Potential

In females of reproductive potential, any Lymphoseek administration should be performed within the ten days following the onset of menses or a pregnancy test should be performed within 48 hours prior to the administration.

11.1 Physical Characteristics

Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours. The principal photon that is useful for detection and imaging studies is listed in Table 6.

11.2 External Radiation

The linear mass energy absorption attenuation coefficient for Tc 99m is 18.986 cm-1. The first half-value layer is 0.037 cm of lead (Pb). The use of a 0.25 cm thick standard radiation lead shield will attenuate the radiation emitted by millicurie amounts of technetium Tc 99m by a factor of about 100. A range of values for the relative attenuation of the radiation of technetium Tc 99m that results with various thicknesses of lead shielding are displayed in Table 7.

To correct for physical decay of the radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 8. 

12.1 Mechanism of Action

Lymphoseek is a radioactive diagnostic agent.  It accumulates in lymphatic tissue and selectively binds to mannose binding receptor (CD206) located on the surface of macrophages and dendritic cells. 

Lymphoseek (tilmanocept) is a macromolecule consisting of multiple units of diethylenetriaminepentaacetic acid (DTPA) and mannose, each covalently attached to a 10 kDa dextran backbone.  The mannose acts as a ligand for the receptor, and the DTPA serves as a chelating agent for labeling with technetium Tc 99m.

12.2 Pharmacodynamics

In in vitro studies, Lymphoseek exhibited binding to human mannose binding receptor with a primary binding site affinity of Kd = 2.76 x 10-11 M.

In clinical studies, Lymphoseek has been detectable in lymph nodes within 10 minutes and up to 30 hours after injection.  It is recommended that intraoperative lymphatic mapping be conducted between 15 minutes and 15 hours following injection.

12.3 Pharmacokinetics

In dose-ranging clinical studies, injection site clearance rates were similar across all Lymphoseek doses (4 to 200 mcg) with a mean elimination rate constant in the range of 0.222 to 0.396/hr, resulting in a drug half-life at the injection site of 1.75 to 3.05 hours.

The amount of the accumulated radioactive dose in the liver, kidney, and bladder reached a maximum 1 hour post administration of Lymphoseek and was approximately 1% to 2% of the injected dose in each tissue.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to assess the carcinogenicity potential of  tilmanocept have not been conducted.  Tilmanocept was not mutagenic in vitro in the Ames bacterial mutation assay and in the in vitro mouse lymphoma test, and was negative in the in vivo micronucleus test in mice.

Studies on reproductive fertility have not been conducted.