IC-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 Dosage and Administration ( 2.5 ) 01/2026

1 INDICATIONS AND USAGE • 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 IC-GREEN 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 IC-GREEN 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 IC-GREEN 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 IC-GREEN is indicated for use in ophthalmic angiography in adults and pediatric patients.

2 DOSAGE AND ADMINISTRATION • Visualization of vessels, blood flow and tissue perfusion (2.5 mg/mL solution) o 1.25 mg to 5 mg by intravenous injection is recommended for a surgical procedure in adults and pediatric patients aged 1 month and older. o 3.75 mg to 10 mg by intravenous injection is recommended for visualization of perfusion in extremities through the skin for plastic, micro- and reconstructive surgeries in adults. o Additional doses may be administered. Do not exceed a total dose of 2 mg/kg. ( 2.1 ) • Visualization of extrahepatic biliary ducts in adults and pediatric patients aged 12 years and older (2.5 mg/mL solution) o 2.5 mg by intravenous injection at least 45 minutes prior to surgery. o Additional doses may be administered. Do not exceed a total dose of 2 mg/kg. ( 2.2 ) • Lymphatic mapping of cervical and uterine cancer in adults (1.25 mg/mL solution) o 5 mg interstitially as four 1 mL injections. o See Full Prescribing Information for injection techniques. ( 2.3 ) • Ophthalmic Angiography o Doses up to 40 mg in 2 mL of Sterile Water for Injection by intravenous injection. ( 2.4 ) • See Full Prescribing Information for reconstitution instructions. ( 2.5 ). 2.1 Recommended Dose, Administration and Imaging for Visualization of Vessels, Blood Flow and Tissue Perfusion Dosing Adults: The recommended dose of IC-GREEN for a single image sequence for visualization of vessels, blood flow and tissue perfusion in adults is 1.25 mg to 5 mg administered intravenously as 0.5 mL to 2 mL of a 2.5 mg/mL solution. For visualization of perfusion in extremities through the skin in adults, the recommended dose is 3.75 mg to 10 mg administered intravenously as 1.5 mL to 4 mL of a 2.5 mg/mL solution. Immediately flush with a 10 mL bolus of 0.9% Sodium Chloride Injection. Pediatric patients aged 1 month and older: The recommended dose of IC-GREEN for a single image sequence for visualization of vessels, blood flow and tissue perfusion in pediatric patients aged 1 month and older is 1.25 mg to 5 mg administered intravenously as 0.5 mL to 2 mL of a 2.5 mg/mL solution. Lower doses may be administered in younger patients and in those with lower body weight. Adjust the amount and type of flush to avoid volume and/or sodium overload. In both adults and pediatric patients aged 1 month and older, additional doses may be administered to obtain imaging sequences during the procedure. Do not exceed the maximum total dose of 2 mg/kg. Administration Prior to the imaging procedure, draw up the desired dose of IC-GREEN solution into appropriate syringes and prepare a 10 mL syringe of 0.9% Sodium Chloride Injection. Administer via a central or peripheral venous line using a three-way stopcock attached to an injection port on the infusion line. Inject the prepared IC-GREEN into the line as a tight bolus. Immediately switch the access on the stopcock and inject the prepared flush. Imaging Instructions IC-GREEN may be used with an FDA-authorized imaging device that is intended to be used with indocyanine green for fluorescence imaging of vessels, blood flow and tissue perfusion. A fluorescence response should be visible in blood vessels within 5 seconds to 15 seconds after injection . 2.2 Recommended Dose, Administration and Imaging for Visualization of Extrahepatic Biliary Ducts Dosing and Administration The recommended dose of IC-GREEN for visualization of extrahepatic biliary ducts in adults and pediatric patients aged 12 years and older is 2.5 mg administered intravenously as 1 mL of a 2.5 mg/mL solution at least 45 minutes prior to surgery. Additional doses may be administered to obtain imaging sequences during the procedure. Do not exceed a total dose of 2 mg/kg. Imaging Instructions IC-GREEN may be used with an FDA-authorized imaging device that is intended to be used with indocyanine green for fluorescence imaging of extrahepatic biliary ducts. Fluorescence is visible in the biliary tree within 45 minutes after injection. 2.3 Recommended Do …

3 DOSAGE FORMS AND STRENGTHS For injection: 25 mg of indocyanine green as a sterile, lyophilized, green powder for reconstitution provided in a 25 mL single-patient-use vial. For injection: 10 mg of indocyanine green as a sterile, lyophilized, green powder for reconstitution provided in a 15 mL single-patient-use vial. For injection: 10 mg and 25 mg of indocyanine green as a lyophilized, green powder for reconstitution in a single-patient-use vial ( 3 )

4 CONTRAINDICATIONS IC-GREEN is contraindicated in patients with a history of hypersensitivity to indocyanine green. Reactions have included anaphylaxis [see Warnings and Precautions ( 5.1 )] . Hypersensitivity to indocyanine green ( 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 IC-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 Diagnostic Green LLC at 1-844-424-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Interference with Thyroid Radioactive Iodine Uptake Studies Because IC-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 IC-GREEN. Interference with Thyroid Radioactive Iodine Uptake Studies: Do not perform radioactive iodine uptake studies for at least one week following the use of IC-GREEN. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of IC-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 IC-GREEN and any potential adverse effects on the breastfed infant from IC-GREEN or from the underlying maternal condition. 8.4 Pediatric Use Use of IC-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 IC-GREEN for visualization of vessels, blood flow and tissue perfusion has not been established in pediatric patients aged less than 1 month. Use of IC-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 IC-GREEN for visualization of extrahepatic biliary ducts has not been established in pediatric patients aged less than 12 years. Use of IC-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 IC-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 safety or effectiveness were observed between these patients and younger patie …

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 IC-GREEN (indocyanine green for injection) is an optical imaging agent for intravenous or interstitial use. Each vial contains 10 mg or 25 mg of indocyanine green with not more than 5% sodium iodide as a sterile, lyophilized, green powder. IC-GREEN has a pH of 5.5-7.5 when reconstituted with Sterile Water for Injection, USP. 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. Molecular Formula: C43H47N2NaO6S2; Molecular Mass: 774.96 g/mol, with the following structural formula: Indocyanine green has a peak spectral absorption at 805 nm in blood. Structural Formula

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied 10 mg/vial: IC-GREEN (indocyanine green for injection) is supplied as a kit (NDC 70100-810-02) containing the following: • Six 15 mL single-patient-use vials of IC-GREEN (10 mg each) as a sterile, lyophilized green powder for reconstitution NDC 70100-710-01 • Six single-dose vials of Sterile Water for Injection (10 mL each) NDC 0409-4887-17 or NDC 0641-6147-10 25 mg/vial: IC-GREEN (indocyanine green for injection) is supplied as a kit (NDC 70100-825-02) containing the following: • Six 25 mL single-patient-use vials of IC-GREEN (25 mg each) as a sterile, lyophilized green powder for reconstitution NDC 70100-725-01 • Six single-dose vials of Sterile Water for Injection (10 mL each) NDC 63323-185-10 or NDC 0409-4887-17 or NDC 0641-6147-10 Storage and Handling Store at 20°C to 25°C (68°F to 77°F).