Indocyanine Green

Indications and Usage, For determining Cardiac Output, Hepatic Function, and Liver Blood Flow (1.1) Removed 12/2024 Indications and Usage ( 1.1 , 1.2 , 1.3 ) 12/2024 Dosage and Administration, Indicator-Dilution Studies and Hepatic Function Studies (2.1, 2.2) Removed 12/2024 Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.5 ) 12/2024

1 INDICATIONS AND USAGE Indocyanine green for injection is an optical imaging agent indicated for: Fluorescence imaging of vessels (micro-and macro-vasculature), blood flow and tissue perfusion before, during and after vascular, gastrointestinal, organ transplant, plastic, micro- and reconstructive surgeries, including general minimally invasive surgical procedures, in adults and pediatric patients aged 1 month and older ( 1.1 ) Fluorescence imaging of extrahepatic biliary ducts in adults and pediatric patients aged 12 years and older ( 1.2 ) Fluorescence imaging of lymph nodes and lymphatic vessels during lymphatic mapping in adults with cervical and uterine cancer ( 1.3 ) Ophthalmic angiography in adults and pediatric patients ( 1.4 ) 1.1 Visualization of Vessels, Blood Flow and Tissue Perfusion Indocyanine green for injection is indicated for fluorescence imaging of vessels (micro- and macro- vasculature), blood flow and tissue perfusion before, during and after vascular, gastrointestinal, organ transplant, plastic, micro- and reconstructive surgeries, including general minimally invasive surgical procedures in adults and pediatric patients aged 1 month and older. 1.2 Visualization of Extrahepatic Biliary Ducts Indocyanine green for injection is indicated for fluorescence imaging of extrahepatic biliary ducts in adults and pediatric patients aged 12 years and older. 1.3 Lymphatic Mapping of Cervical and Uterine Cancer Indocyanine green for injection is indicated for fluorescence imaging of lymph nodes and delineation of lymphatic vessels during lymphatic mapping in adults with cervical and uterine cancer for which this procedure is a component of intraoperative management. 1.4 Ophthalmic Angiography Indocyanine green for injection is indicated for use in ophthalmic angiography in adults and pediatric patients.

2 DOSAGE AND ADMINISTRATION For visual assessment of blood vessels, blood flow and related tissue perfusion ( 2.1 ) Under sterile conditions, the Indocyanine Green for Injection USP powder should be dissolved with the 10 mL Sterile Water for Injection, USP provided and the solution used within 6 hours after it is prepared. The usual doses of Indocyanine Green for Injection USP is 0.1 mg/kg (0.04 mL/kg) – 0.3 mg/kg (0.12 mL/kg). Immediately follow each ICG intravenous injection with a tight bolus injection of approximately 10 - 12 mL of normal saline immediately before IR imaging. Multiple administrations can be performed, up to 2 mg/kg (0.8 mL/kg) per patient. For visual assessment of the major extrahepatic bile ducts ( 2.2 ) Under sterile conditions, the Indocyanine Green for Injection USP powder should be dissolved with the 10 mL Sterile Water for Injection, USP provided and the solution used within 6 hours after it is prepared. The usual doses of Indocyanine Green for Injection USP is 3.0 mg (1.2 mL). Immediately follow each ICG intravenous injection with a tight bolus injection of approximately 10 - 12 mL of normal saline at least 30 minutes prior to IR imaging. Multiple administrations can be performed, up to 2 mg/kg (0.8 mL/kg) per patient. For viewing intra-operative blood flow in the cerebral area ( 2.3 ) Under sterile conditions, the Indocyanine Green for Injection USP powder should be dissolved with the 10 mL Sterile Water for Injection, USP provided and the solution used within 6 hours after it is prepared. The usual doses of Indocyanine Green for Injection USP is 0.1 mg/kg (0.04 mL/kg) – 0.3 mg/kg (0.12 mL/kg). Immediately follow each ICG intravenous injection with a tight bolus injection of approximately 10 - 12 mL of normal saline immediately before IR imaging Multiple administrations can be performed, up to 2 mg/kg (0.8 mL/kg) per patient. 2.1 Visual assessment of blood vessels, blood flow and related tissue perfusion Under sterile conditions, the Indocyanine Green for Injection USP powder should be dissolved with the 10 mL Sterile Water for Injection, USP provided for this product, and the solution used within 6 hours after it is prepared. If a precipitate is present, discard the solution. The patient should be weighed and the dosage for one administration should be calculated on the basis of 0.1 mg/kg (0.04 mL/kg) - 0.3 mg/kg (0.12 mL/kg) of body weight. Multiple administrations can be performed, up to 2 mg/kg (0.8 mL/kg) per patient. ICG should be administrated immediately before IR imaging. Item Note Indocyanine Green for Injection, USP 25 mg vials of ICG powder Sterile Water for Injection (for dissolving ICG) 10 mL vial of sterile water Syringe (for injecting sterile water into the ICG vial) Use the syringe whose minimum volume is 10 mL Syringes (for each administration) Considering the administration volume, select the appropriate size Sterile normal saline (for each saline flush) Approximately 10 – 12 mL following each ICG administration Syringes (for each saline flush) Use the syringe whose minimum volume is 12 mL Prepare the syringes filled with the weight-scaled dose of ICG solution, and the syringes filled with 10 - 12 mL of normal saline for the tight bolus injection. Immediately before IR imaging, administer the prepared dose of ICG solution intravenously. Immediately follow each ICG injection with a tight bolus injection of approximately 10 - 12 mL of normal saline. 2.2 Visual assessment of the major extrahepatic bile duct Under sterile conditions, the Indocyanine Green for Injection USP powder should be dissolved with the 10 mL Sterile Water for Injection, USP provided for this product, and the solution used within 6 hours after it is prepared. If a precipitate is present, discard the solution. The dosage for one administration should be 3.0 mg (1.2 mL) per patient. Multiple administration can be performed, up to 2 mg/kg (0.8 mL/kg) per patient. ICG should be administrated at least 30 minutes prio …

3 DOSAGE FORMS AND STRENGTHS For injection: 25 mg of indocyanine green as a sterile, lyophilized, dark green, blue-green, dark blue, olive-brown or black color cake or powder for reconstitution provided in a 20 mL single-patient-use vial. For injection: 25 mg of indocyanine green as a lyophilized, dark green, blue-green, dark blue, olive-brown or black color cake or powder for reconstitution in a single-patient-use vial ( 3 )

4 CONTRAINDICATIONS Indocyanine Green for Injection USP contains sodium iodide and should be used with caution in patients who have a history of allergy to iodides because of the risk of anaphylaxis. Indocyanine Green for Injection USP contains sodium iodide and should be used with caution in patients who have a history of allergy to iodides because of the risk of anaphylaxis. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] . The following adverse reactions have been identified during post-approval use of indocyanine green. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : Anaphylaxis, urticaria The most common adverse reactions reported are anaphylaxis and urticaria. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www fda.gov/medwatch.

7 DRUG INTERACTIONS Interference with Thyroid Radioactive Iodine Uptake Studies Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green. Interference with Thyroid Radioactive Iodine Uptake Studies: Do not perform radioactive iodine uptake studies for at least one week following the use of indocyanine green. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of indocyanine green in pregnant women. Available data from a very small number of scientific literature studies with indocyanine green use in pregnant women over several decades have not reported any drug associated risks for major birth defects, miscarriage or adverse maternal or fetal outcomes. Data from one small study in which indocyanine green was administered intravenously to pregnant women during labor suggest there is no placental transfer of the drug. Animal reproduction studies have not been conducted with indocyanine green. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Seventeen cases of indocyanine green use in lactating women have been reported in the scientific literature with no adverse events observed in the breastfed infant. However, there are no data on the presence of indocyanine green in human milk or the effects on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for indocyanine green and any potential adverse effects on the breastfed infant from indocyanine green or from the underlying maternal condition. 8.4 Pediatric Use Use of indocyanine green for visualization of vessels, blood flow and tissue perfusion has been established in pediatric patients aged 1 month and older. Pediatric use is supported by published data in 49 pediatric patients who received indocyanine green for assessment of blood flow and tissue perfusion in cardiovascular, vascular and plastic, micro- and reconstructive surgical procedures and by clinical trials in adults . No overall differences in safety or effectiveness have been observed between pediatric patients and adults. The dose range was similar to the effective dose range in adults [see Dosage and Administration ( 2.1 )]. The use of indocyanine green for visualization of vessels, blood flow and tissue perfusion has not been established in pediatric patients aged less than 1 month. Use of indocyanine green for visualization of extrahepatic biliary ducts has been established in pediatric patients aged 12 years and older. Pediatric use is supported by clinical trials in adults in addition to clinical use in pediatric patients. No overall differences in safety or effectiveness have been observed between pediatric patients and adults. The dose range was similar to the effective dose range in adults [see Dosage and Administration ( 2.2 )] . The use of indocyanine green for visualization of extrahepatic biliary ducts has not been established in pediatric patients aged less than 12 years. Use of indocyanine green for visualization of lymph nodes and lymphatic vessels during lymphatic mapping for cervical and uterine cancer have not been established in pediatric patients. Use of indocyanine green for ophthalmic angiography has been established in pediatric patients. Pediatric use is supported by evidence from the published literature. 8.5 Geriatric Use Of the total number of patients in clinical studies of indocyanine green for injection for visualization of vessels, blood flow and tissue perfusion, 7% were 65 and over, while 1% were 75 and over. Of the total number of patients in clinical studies of indocyanine green for injection for visualization of lymph nodes and lymphatic vessels during lymphatic mapping of cervical and uterine cancer, 9% were 65 and over, while 2% were 75 and over. Clinical studies of indocyanine green for injection for visualization of extrahepatic biliary ducts did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. No overall differences in …

12.1 Mechanism of Action When bound to proteins in plasma or in lymph fluid, indocyanine green absorbs light in the near-infrared region with peak absorption at 805 nm and emits fluorescence (light) at a slightly longer wavelength, with peak emission at 830 nm. Fluorescence imaging devices provide external energy as near infrared light for indocyanine green to absorb, resulting in excitation of the indocyanine green, and the emitted light (fluorescence) is transferred from the field of view to an image on a monitor. These optical properties of indocyanine green are utilized in fluorescence imaging of the micro- and macro-vasculature, blood flow and tissue perfusion, the extrahepatic biliary ducts, and for lymphatic mapping of lymph nodes and lymphatic vessels.

11 DESCRIPTION Indocyanine Green for Injection USP is a sterile, lyophilized green powder containing 25 mg of indocyanine green with no more than 5% sodium iodide. It is packaged with Sterile Water for Injection, USP used to dissolve the indocyanine green. Indocyanine Green for Injection USP is to be administered intravenously. Indocyanine green is a water soluble, tricarbocyanine dye with a peak spectral absorption at 800 nm. The chemical name for Indocyanine Green is 1 H -Benz[ e ]indolium, 2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2 H -benz[ e ] indol-2-ylidene]-1,3,5-heptatrienyl]-1,1-dimethyl-3-(4-sulfobutyl)-,hydroxide, inner salt, sodium salt. Indocyanine Green for Injection USP has a pH of approximately 6.5 when reconstituted. Each vial of Indocyanine Green for Injection USP contains 25 mg of indocyanine green as a sterile lyophilized powder. Structure

10 OVERDOSAGE There are no data available describing the signs, symptoms, or laboratory findings accompanying overdosage. The LD50 after intravenous administration ranges between 60 and 80 mg/kg in mice, 50 and 70 mg/kg in rats and 50 and 80 mg/kg in rabbits. Based on body surface area, these doses are 2.4 to 13-fold the maximum recommended human (MRHD) dose of 2 mg/kg for indicator-dilution studies, 10 to 52-fold the MRHD of 0.5 mg/kg for hepatic-function studies, and 7 to 39-fold the MRHD of 0.67 mg/kg for ophthalmic angiography studies.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Indocyanine green for injection, USP is supplied as a kit (NDC 70710-2018-3) containing the following: Six 20 mL single-patient-use vials of indocyanine green for injection, USP (25 mg each) as a sterile, lyophilized, dark green, blue-green, dark blue, olive-brown or black color cake or powder for reconstitution NDC 70710-2031-1 Carton (NDC 70710-2032-8) containing six single-dose vials (NDC 70710-2032-1) of Sterile Water for Injection, USP (10 mL each) Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [see USP Controlled Room Temperature]