1.1 Visualization of Vessels, Blood Flow and Tissue Perfusion

Indocyanine 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

Indocyanine 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

Indocyanine 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

Indocyanine Green is indicated for use in ophthalmic angiography in adults and pediatric patients.

2.1 Indicator-Dilution Studies

Dosing

Adults:

The recommended dose of Indocyanine 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 Indocyanine 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 Indocyanine 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 Indocyanine Green into the line as a tight bolus. Immediately switch the access on the stopcock and inject the prepared flush.

Imaging Instructions

Indocyanine 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 Indocyanine 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

Indocyanine 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 Dose, Administration and Imaging for Lymphatic Mapping of Cervical and Uterine Cancer

Dosing and Administration

The recommended dose of Indocyanine Green for lymphatic mapping of cervical and uterine cancer in adults is 5 mg administered interstitially as four 1 mL injections of a 1.25 mg/mL solution into the cervix, at the 3 o’ clock and the 9 o’clock positions with a superficial (1 mm to 3 mm) and a deep (1 cm to 3 cm) injection at each position.

Imaging Instructions

Indocyanine Green may be used with an FDA-authorized imaging device that is intended to be used with indocyanine green for fluorescence imaging of lymph nodes and delineation of lymphatic vessels during lymphatic mapping of cervical and uterine cancer.

Fluorescent lymphatic vessels and lymph nodes should begin to be visible within 1 minute after injection.

2.4 Recommended Dose and Administration for Ophthalmic Angiography

Dosing and Administration

Doses up to 40 mg Indocyanine Green in 2 mL of Sterile Water for Injection depending on the imaging equipment and technique used should be administered intravenously and immediately followed by a 5 mL bolus of 0.9% Sodium Chloride Injection. The antecubital vein can be used for Indocyanine Green administration.

2.5 Reconstitution Instructions

General

•

Prepare Indocyanine Green for injection using aseptic techniques prior to procedure.

•

Inspect the reconstituted solution for particulate matter. The reconstituted solution should be a clear, green solution.

•

Use the prepared solution within 6 hours.

•

Discard any unused product.

Visualization of Vessels, Blood Flow, Tissue Perfusion and Extrahepatic Biliary Ducts

Dissolve 25 mg of Indocyanine Green with 10 mL Sterile Water for Injection to form a concentration of 2.5 mg/mL indocyanine green.

Lymphatic Mapping of Cervical and Uterine Cancer

Dissolve 25 mg of Indocyanine Green with 20 mL Sterile Water for Injection to form a concentration of 1.25 mg/mL indocyanine green.

Ophthalmic Angiography

Dissolve doses up to 40 mg of Indocyanine Green with 2 mL Sterile Water for Injection.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions including anaphylaxis, urticaria and deaths due to anaphylaxis have been reported following intravenous administration of Indocyanine Green [see Adverse Reactions (6)].

Indocyanine Green is contraindicated in patients with a history of hypersensitivity to indocyanine green [see Contraindications (4)]. Always have cardiopulmonary resuscitation personnel and equipment readily available and monitor all patients for hypersensitivity reactions.

5.2 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 [see Drug Interactions (7)].

8.1 Pregnancy

8.2 Lactation

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 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 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 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 patients, and other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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.

12.2 Pharmacodynamics

There are no pharmacodynamic data.

12.3 Pharmacokinetics

Distribution

Following intravenous injection, indocyanine green binds to plasma proteins (98%) and is largely confined to the intravascular compartment. Indocyanine green undergoes no significant extrahepatic or enterohepatic circulation; simultaneous arterial and venous blood estimations have shown negligible renal, peripheral, lung or cerebro-spinal uptake of the dye. After biliary obstruction, the dye appears in the hepatic lymph, independently of the bile, suggesting that the biliary mucosa is sufficiently intact to prevent diffusion of the dye, though allowing diffusion of bilirubin.

Following interstitial injection, indocyanine green binds to proteins in lymph fluid and the interstitial space, is taken up by the lymphatic vessels, and drains to the lymph nodes.

Since excessive dye extravasation does not take place in the highly fenestrated choroidal vasculature, Indocyanine Green is useful in both absorption and fluorescence infrared angiography of the choroidal vasculature when using appropriate filters and film in a fundus camera.

Elimination

Indocyanine green is taken up from the plasma almost exclusively by the hepatic parenchymal cells and is secreted entirely into the bile.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to evaluate the potential for carcinogenicity, mutagenicity, or impairment of fertility by indocyanine green.

14.1 Lymphatic Mapping of Cervical and Uterine Cancer

The effectiveness of Indocyanine Green for fluorescence imaging of lymph nodes and delineation of lymphatic vessels during lymphatic mapping in adults with cervical and uterine cancer has been established based on a study of another formulation of indocyanine green for injection. Below is a description of the FILM Study (NCT 02209532).

The study was a randomized, prospective, multi-center, open-label study in patients with early stage uterine or cervical cancer and no known regional nodal or metastatic disease by standard clinical evaluation. Indocyanine green and a blue dye comparator were injected into the cervix of patients at the beginning of the operative procedure.

A total of 176 patients were randomized to receive either indocyanine green followed by blue dye or blue dye followed by indocyanine green. A total of four 1 mL injections of a 1.25 mg/ml solution of indocyanine green for a total dose of 5 mg were administered interstitially into the cervix at the 3 o'clock and 9 o'clock positions with a superficial (1 mm to 3 mm) and a deep (1 cm to 3 cm) injection at each position.

Lymphatic mapping was performed intraoperatively using a fluorescence imaging device and standard light, followed by excision of tissues identified by indocyanine green, blue dye, or the surgeon's visual and palpation examination. The resected tissues were evaluated by histopathology to confirm presence of lymph nodes. The efficacy of indocyanine green in the detection of lymphatic vessels and lymph nodes during lymphatic mapping procedures was determined by the number of histology-confirmed lymph nodes detected by indocyanine green and/or the blue dye comparator.

The mean age of the 176 patients was 63 years (range: 31 to 88 years); distribution by race and ethnicity was 79% White, 4% Black or African American, 3% Asian, 13% Hispanic/Latino and 1% other.

Table 1 shows the distribution of resected, confirmed lymph nodes detected by indocyanine green or blue dye in the modified intent-to-treat population (mlTT). Among the confirmed lymph nodes identified, 93% were identified using indocyanine green, and 43% were identified using blue dye, a difference of 50% [95% confidence interval 39% to 60%].

Table 2 shows the number of patients with at least one resected, confirmed lymph node and the number of patients with at least one bilateral lymph node pair detected by indocyanine green or blue dye. With indocyanine green, approximately 97% of patients had at least one resected, confirmed lymph node detected and 73% had at least one bilateral lymph node pair detected, compared with 68% and 28%, respectively, with blue dye (p-values for each analysis <0.0001).