Indocyanine Green: Package Insert / Prescribing Info

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 1shows 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 2shows 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).