Tilmanocept

INDICATIONS AND USAGE Lymphoseek is a radioactive diagnostic agent indicated with or without scintigraphic imaging for: • Lymphatic mapping using a handheld gamma counter to locate lymph nodes draining a primary tumor site in adult and pediatric patients age one month and older with solid tumors for which this procedure is a component of intraoperative management. • Guiding sentinel lymph node biopsy using a handheld gamma counter in patients with clinically node negative squamous cell carcinoma of the oral cavity, breast cancer or melanoma. Lymphoseek is a radioactive diagnostic agent indicated with or without scintigraphic imaging for: • Lymphatic mapping using a handheld gamma counter to locate lymph nodes draining a primary tumor site in adult and pediatric patients age one month and older with solid tumors for which this procedure is a component of intraoperative management. ( 1 ) • Guiding sentinel lymph node biopsy using a handheld gamma counter in patients with clinically node negative squamous cell carcinoma of the oral cavity, breast cancer or melanoma. ( 1 )

DOSAGE AND ADMINISTRATION • Lymphoseek is supplied as a kit and must be prepared by radiolabeling with technetium Tc 99m and diluting with the supplied diluent or pharmacy-available sterile 0.9% sodium chloride injection prior to use. ( 2.3 ) • Use aseptic technique and radiation safety precautions during Lymphoseek preparation and handling. Determine the total injection volume and number of sites to be injected for each patient before preparing Lymphoseek. ( 2.1 , 2.3 ) • Recommended dose of Lymphoseek is 18.5 MBq (0.5 mCi) administered at least 15 minutes before initiating intraoperative lymphatic mapping or sentinel node biopsy procedures: complete these procedures within 15 hours of Lymphoseek injection. ( 2.2 , 2.3 ) • Recommended routes of administration are intradermal, subcutaneous, subareolar, or peritumoral. ( 2.3 ) • Use radiolabeled Lymphoseek within 6 hours of its preparation. ( 2.3 ) • See Full Prescribing Information for important preparation and administration instructions. ( 2 ) 2.1 Radiation Safety - Drug Handling Lymphoseek is a radioactive drug and should be handled with appropriate safety measures to decrease 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 Dosing The recommended dose of Lymphoseek is 18.5 MBq (0.5 mCi) as a radioactivity dose and 50 mcg as a mass dose. Administer Lymphoseek at least 15 minutes prior to initiating intraoperative lymphatic mapping and sentinel node biopsy; complete these procedures within 15 hours after Lymphoseek injection. Route of Administration and Injection Method The route of administration depends on the tumor location and the planned injection technique and includes: subcutaneous, intradermal, subareolar, or peritumoral injection. Lymphoseek may be administered to a patient as a single injection or as multiple injections. 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). 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. In animal studies, locally injected anesthetics have been reported to reduce lymphatic flow. Concomitant administration of local anesthetics with Lymphoseek is not recommended and may impair the lymph nodal mapping. 2.3 Drug Preparation General Considerations • Lymphoseek (kit for the preparation of technetium Tc 99m tilmanocept injection) contains five vials, each containing 250 mcg of tilmanocept from which 50 mcg is intended for administration to a patient. o The Lymphoseek kit is packaged either with or without five DILUENT for Lymphoseek vials each containing 4.5 mL of sterile buffered saline with phenol. o The Lymphoseek kit may also be diluted with pharmacy-available sterile 0.9% sodium chloride injection. o A diluent 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 Lymphoseek kit 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. Drug Preparation Instructions 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. Table 1. Preparation of Lymphoseek for Administration Planned Number of Injections for a Patient Total Injection Volume Per Patient Reconstituted Vial Volume of Radiolabeled Lymphoseek 1 syringe x 0.1 mL 0.1 mL 0.5 mL 5 syringes x 0.1 mL or 2 syringes x 0.25 mL or 1 syringe x 0.5 mL 0.5 mL 2.5 mL 5 syringes x 0.2 mL or 4 syringes x 0.25 mL or 2 syringes x 0.5 mL 1 mL 5 mL Once the Reconstituted Vial Volume is established, use the following steps to prepare radiolabeled Lymphoseek: Radiolabeling a. Inspect the Lymphoseek vial for any damage. Do not use if vial integrity appears compromised. Do not vent the Lymphoseek vial prior to or during radiolabeling. b. Use Sodium Pertechnetate Tc 99m Injection from a technetium Tc 99m generator within 8 hours of its elution. c. Using a sterile syringe, aseptically draw approximately 92.5 MBq (2.5 mCi) of Sodium Pertechnetate Tc 99m Injection 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. d. 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 Lymphoseek vial. Place the vial in a radiation shield and sanitize the septum with alcohol wipe. e. Aseptically add Sodium Pertechnetate Tc 99m Injection to the Lymphoseek vial. Without withdrawing the needle, remove an equal volume of headspace gas. Do not vent. f. Remove the needle, gently shake the vial to mix the contents, and then let it stand at room temperature for at least 15 minutes. Reconstitution g. Aseptically add the supplied DILUENT for Lymphoseek or pharmacy-available sterile 0.9% sodium chloride injection to the radiolabeled product in the Lymphoseek 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. h. Each Lymphoseek vial, once radiolabeled and reconstituted, would contain sufficient amount to provide doses for up to four patients when prepared according to the instructions. Quality Control of Radiolabeled Solution 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 radiolabeled product [see Dosage and Administration ( 2.4 )] . Do not use if the radiochemical purity is less than 90%. k. Withdraw the required volume of the radiolabeled 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). Duration of Use and Storage of Radiolabeled Solution l. Store the radiolabeled Lymphoseek in radiation shielding at room temperature. m. Use the radiolabeled Lymphoseek within 6 hours of preparation. Discard the unused radiolabeled Lymphoseek. 2.4 Determination of Radiochemical Purity of Radiolabeled Lymphoseek Determine radiochemical purity of the reconstituted radiolabeled Lymphoseek by Instant Thin Layer Chromatography (ITLC) usin

WARNINGS AND PRECAUTIONS Hypersensitivity: Ask patients about prior reactions to drugs, especially dextran or modified forms of dextran. Observe for hypersensitivity signs and symptoms following Lymphoseek injection. Have resuscitation equipment and trained personnel immediately available. ( 5.1 ) 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). Before administering Lymphoseek, ask patients about prior hypersensitivity 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 decrease the risk for excessive radiation exposure to either patients or health care workers.

CONTRAINDICATIONS None. None. ( 4 )

ADVERSE REACTIONS The most common adverse reactions (incidence < 1%) are injection site irritation and/or pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cardinal Health at 1-800-618-2768 or www.lymphoseek.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 open label, single arm clinical trials, 553 adult patients with either breast cancer, melanoma, or squamous cell carcinoma of the oral cavity, skin, and lip received Lymphoseek. No patients experienced serious adverse reactions. Injection site irritation (4 patients; 0.7%) and pain (1 patient; 0.2%) were reported.

Mechanism of Action Lymphoseek (technetium Tc 99m tilmanocept) is a radioactive diagnostic agent. It accumulates in lymphatic tissue and selectively binds to mannose binding receptors (CD206) located on the surface of macrophages and dendritic cells. Technetium Tc 99m 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.