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Technetium Tc 99m Tilmanocept Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 9. MECHANISM OF ACTION
4. CONTRAINDICATIONS 10. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 11. PHARMACOKINETICS
6. ADVERSE REACTIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

The active ingredient in technetium Tc 99m tilmanocept is technetium Tc 99m tilmanocept. The active ingredient is formed when Technetium Tc 99m pertechnetate, sodium injection is added to the tilmanocept powder vial.

Technetium Tc 99m binds to the diethylenetriaminepentaacetic acid (DTPA) moieties of the tilmanocept molecule.

Chemically, technetium Tc 99m tilmanocept consists of technetium Tc 99m, dextran 3-[(2- aminoethyl)thio]propyl 17-carboxy-10,13,16- tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16- tetraazaheptadec-1-yl 3-[[2-[[1-imino-2-(D- mannopyranosylthio) ethyl]amino]ethyl]thio]propyl ether complexes. Technetium Tc 99m tilmanocept has the following structural formula:

Empirical formula: [C6H10O5]n.(C19H28N4O9S99mTc)b.(C13H24N2O5S2)c.(C5H11NS)a

Calculated average molecular weight: 15,281 to 23,454 g/mol

It contains 3-8 conjugated DTPA (diethylenetriamine pentaacetic acid) molecules (b); 12-20 conjugated mannose molecules (c) with 0-17 amine side chains (a) remaining free.

The tilmanocept powder vial contains a sterile, non-pyrogenic, white to off-white powder that consists of a mixture of 250 mcg tilmanocept, 20 mg trehalose dihydrate, 0.5 mg glycine, 0.5 mg sodium ascorbate, and 0.075 mg stannous chloride dihydrate. The contents of the vial are lyophilized and are under nitrogen.

Technetium Tc 99m tilmanocept injection is supplied as a Kit. The Kit includes tilmanocept powder vials which contain the necessary non-radioactive ingredients needed to produce technetium Tc 99m tilmanocept. The Kit also contains DILUENT for technetium Tc 99m tilmanocept. The diluent contains a preservative and is specifically formulated for technetium Tc 99m tilmanocept. No other diluent should be used.

The DILUENT for technetium Tc 99m tilmanocept contains 4.5 mL sterile buffered saline consisting of 0.04% (w/v) potassium phosphate, 0.11% (w/v) sodium phosphate (heptahydrate), 0.5% (w/v) sodium chloride, and 0.4% (w/v) phenol. The pH is 6.8 – 7.2.

1.1 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 1.

Table 1. Principal Radiation Emission Data

From: Kocher, D.C. Radioactive decay data tables. DOE/TIC-11026, 108 (1981).

1.2 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 2.

Table 2. Radiation Attenuation by Lead Shielding

To correct for physical decay of the radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 3.

Table 3. Physical Decay Chart; Tc 99m, Half-Life of 6.02 Hours

2. INDICATIONS AND USAGE

Technetium Tc 99m tilmanocept injection is indicated for lymphatic mapping with a handheld gamma counter to assist in the localization of lymph nodes draining a primary tumor site in patients with breast cancer or melanoma.

3. DOSAGE AND ADMINISTRATION

3.1 Radiation Safety – Drug Handling

Technetium Tc 99m tilmanocept 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 technetium Tc 99m tilmanocept.

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.

3.2 Recommended Dose

The recommended dose of technetium Tc 99m tilmanocept 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).

3.3 Drug Preparation and Administration

General Considerations:

• Kit for the preparation of technetium Tc 99m tilmanocept contains five sets of two vials: a tilmanocept powder vial and a DILUENT for technetium Tc 99m tilmanocept vial.

o Tilmanocept powder vial contains 250 mcg of tilmanocept from which 50 mcg is intended for administration to a patient.

o The DILUENT for technetium Tc 99m tilmanocept vial contains 4.5 mL of sterile buffered saline. It is used to dilute technetium Tc 99m tilmanocept 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 technetium Tc 99m tilmanocept are sterile, non-pyrogenic, and are intended solely for use in the preparation of 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 technetium Tc 99m tilmanocept to prevent radiation exposure.

Drug Preparation Instructions:

Technetium Tc 99m tilmanocept may be administered to a patient as a single injection or as multiple injections. Prior to preparation of technetium Tc 99m tilmanocept, 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 4 below) the Reconstituted Vial Volume of radiolabeled technetium Tc 99m tilmanocept.

Table 4. Preparation of Technetium Tc 99m Tilmanocept for Administration

Each technetium Tc 99m tilmanocept 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 technetium Tc 99m tilmanocept is to be used within 6 hours of its preparation. Discard the unused radiolabeled technetium Tc 99m tilmanocept.

Once the Reconstituted Vial Volume is established, use the following steps to prepare radiolabeled technetium Tc 99m tilmanocept:

a. Prior to radiolabeling, inspect the Tilmanocept Powder vial for any damage. Do not use if vial integrity appears compromised.

b. For radiolabeling, use Technetium Tc 99m pertechnetate, sodium injection 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 radiolabeling.

d. 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.

e. 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.

f. 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.

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

h. Aseptically add the supplied DILUENT for technetium Tc 99m tilmanocept 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.

i. 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.

j. Determine the radiochemical purity of the reconstituted product as described in 2.4. Do not use if the radiochemical purity is less than 90%.

k. 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).

l. 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 technetium Tc 99m tilmanocept into a patient at least 15 minutes prior to intraoperative lymphatic mapping; do not delay mapping more than 15 hours after technetium Tc 99m tilmanocept injection. Table 5 shows the route of administration options.

Table 5. Technetium Tc 99m Tilmanocept Administration Routes

3.4 Determination of Radiochemical Purity of Radiolabeled Technetium Tc 99m Tilmanocept

Determine radiochemical purity of the reconstituted radiolabeled technetium Tc 99m tilmanocept 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 reconstituted product at the center of the origin line chromatography strip. Let the product spot dry.

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 reconstituted technetium Tc 99m tilmanocept if the radiochemical purity is less than 90%.

3.5 Lymphatic Mapping Procedures Following Injection of Technetium Tc 99m Tilmanocept

• 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.

• 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 technetium Tc 99m tilmanocept, as exemplified in Table 6.

Table 6. Example of Estimates of the Three Sigma Threshold Value

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

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• Technetium Tc 99m tilmanocept is intended to supplement palpation, visual inspection, and other procedures important to lymph node localization. Intraoperative lymphatic mapping by gamma detection of technetium Tc 99m tilmanocept 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 technetium Tc 99m tilmanocept, some were detected only with the blue dye tracer or only with palpation.

• 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.

3.6 Radiation Dosimetry

The radiation doses to organs and tissues of an average patient (70 kg) per 18.5 MBq (0.5 mCi) of technetium Tc 99m tilmanocept are shown in Table 7 and Table 8.

Table 7. Estimated Absorbed Radiation Dose from 50 mcg Technetium Tc 99m Tilmanocept in Patients with Breast Cancera

a Calculated from data of 18 patients with breast cancer who received four peritumoral injections of 4 mcg, 20 mcg, and 100 mcg doses of technetium Tc 99m tilmanocept.

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Table 8. Estimated Absorbed Radiation Dose from 50 mcg Technetium Tc 99m Tilmanocept in Patients with Melanomaa

a Calculated from data of 18 patients with melanoma who received four intradermal injections of 20 mcg, 100 mcg, and 200 mcg doses of technetium Tc 99m tilmanocept.

b Due to the differences in injection sites among patients with melanoma, the injection site was assumed to be the breast for the purposes of this calculation, as it represents the nearest anatomical construct for the skin from the anatomical sites appropriately included in the estimates.

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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.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Technetium Tc 99m tilmanocept may pose a risk of hypersensitivity reactions due to its chemical similarity to dextran. [see Description (1)] 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 technetium Tc 99m tilmanocept, 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 technetium Tc 99m tilmanocept 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. ADVERSE REACTIONS

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 technetium Tc 99m tilmanocept. 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.

7. DRUG INTERACTIONS

In animal studies, locally injected anesthetics have been reported to reduce lymphatic flow. Co-injection (mixture) of local anesthetics with technetium Tc 99m tilmanocept is not recommended and may impair the lymph nodal mapping.

8. USE IN SPECIFIC POPULATIONS

8.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate or well-controlled studies of technetium Tc 99m tilmanocept in pregnant women.

Unbound technetium crosses the placenta. All radiopharmaceuticals, including technetium Tc 99m tilmanocept, 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 technetium Tc 99m tilmanocept. Technetium Tc 99m tilmanocept should be given to a pregnant woman only if clearly needed.

8.2 Nursing Mothers

It is not known whether technetium Tc 99m tilmanocept 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 technetium Tc 99m tilmanocept. Exercise caution when administering technetium Tc 99m tilmanocept to a nursing mother.

8.3 Pediatric Use

Safety and effectiveness of technetium Tc 99m tilmanocept in pediatric patients have not been established.

8.4 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).

8.5 Females of Reproductive Potential

In females of reproductive potential, any technetium Tc 99m tilmanocept 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.

9. MECHANISM OF ACTION

Technetium Tc 99m tilmanocept 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.

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.

10. PHARMACODYNAMICS

In in vitro studies, technetium Tc 99m tilmanocept exhibited binding to human mannose binding receptor with a primary binding site affinity of Kd = 2.76 x 10-11 M.

In clinical studies, technetium Tc 99m tilmanocept 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.

11. PHARMACOKINETICS

In dose-ranging clinical studies, injection site clearance rates were similar across all technetium Tc 99m tilmanocept 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 technetium Tc 99m tilmanocept and was approximately 1% to 2% of the injected dose in each tissue.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: LYMPHOSEEK, by Navidea Biopharmaceuticals Inc.

b) Generic drugs: None.

2) How Supplied:

The Kit for the Preparation of Lymphoseek (technetium Tc 99m tilmanocept) Injection includes:

• Five vials of Tilmanocept Powder, 250 mcg NDC 52579-1695-1

• Five vials of DILUENT for Lymphoseek NDC 52579-1649-1

• Prescribing information

• Five labels for shields

• Twenty-five labels for product vials and individual syringes

3) Storage and Handling:

Store Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) Injection in the original packaging at USP controlled room temperature 20°C - 25°C (68°F - 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Store reconstituted Lymphoseek in radiation shielding at room temperature.

Use reconstituted Lymphoseek within 6 hours of its preparation.

Handling

This Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) Injection is approved for distribution to persons licensed by the U.S. Nuclear Regulatory Commission to use byproduct material identified in 10 CFR 35.200 or under an equivalent license issued by an Agreement State.

Rx only

Rev 03/13