Spy Elite Kit
FDA Label NDC 66259-306

SPY AGENT™ GREEN is indicated in adults and pediatric patients one month of age and older for:

• fluorescence imaging of micro- and macro-vasculature, blood flow and tissue perfusion before, during and after vascular, gastrointestinal, organ transplant, and plastic, micro- and reconstructive surgeries, including general minimally invasive surgical procedures.

SPY AGENT™ GREEN is indicated in adults and pediatric patients aged 12 to 17 years for:

• fluorescence imaging of extrahepatic biliary ducts.

SPY AGENT™ GREEN is indicated in women for:

• fluorescence imaging of lymph nodes and delineation of lymphatic vessels in the cervix and uterus during lymphatic mapping in patients with solid tumors for which this procedure is a component of intraoperative management.

Dosing
Adults:
The recommended dose of SPY AGENT GREEN for a single image sequence is 1.25 mg to 5 mg of a 2.5 mg/mL solution.

For visualization of perfusion in extremities through the skin, the recommended dose is 3.75 mg to 10 mg of a 2.5 mg/mL solution.

Immediately flush with a 10 mL bolus of 0.9% Sodium Chloride, USP.

Pediatric patients:
The recommended dose for a single image sequence is 1.25 mg to 5 mg SPY AGENT GREEN 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.

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 dosage of SPY AGENT GREEN solution into appropriate syringes and prepare a 10 mL syringe of 0.9% Sodium Chloride, USP.

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 SPY AGENT GREEN into the line as a tight bolus. Immediately switch the access on the stopcock and inject the prepared flush.

Imaging Instructions for Visualization of Vessels, Blood Flow and Tissue Perfusion
SPY AGENT GREEN may be used with either the SPY^® Elite or PINPOINT^® Fluorescence Imaging Systems or with a FDA cleared or approved imaging device that is specifically intended for fluorescence imaging with indocyanine green.

A fluorescence response should be visible in blood vessels within 5 to 15 seconds after injection.

Dosing and Administration
The recommended single dose of SPY AGENT GREEN for adults and pediatric patients aged 12 to 17 years is 2.5 mg of a 2.5 mg/mL solution administered intravenously as a single dose 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 for Visualization of Extrahepatic Biliary Ducts
SPY AGENT GREEN may be used with the PINPOINT^® Fluorescence Imaging System or with a FDA cleared or approved imaging device that is specifically intended for fluorescence imaging with indocyanine green.

Fluorescence is visible in the biliary tree within 45 minutes after injection.

Dosing and Administration
The recommended single dose of SPY AGENT GREEN is 5 mg of a 1.25 mg/mL solution (four 1 mL injections administered interstitially into the cervix, at the three o’ clock and the nine 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 for Visualization of Lymph Nodes and Lymphatic Vessels During Lymphatic Mapping
SPY AGENT GREEN may be used with the PINPOINT^® Fluorescence Imaging System or with a FDA cleared or approved imaging device that is specifically intended for fluorescence imaging with indocyanine green.

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

General

• Prepare SPY AGENT GREEN under sterile conditions prior to surgery.
• 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, and Tissue Perfusion and Visualization of Extrahepatic Biliary Ducts

• Dissolve SPY AGENT GREEN with 10 mL Sterile Water for Injection, USP to form a concentration of 2.5 mg indocyanine green/mL.

Visualization of Lymph Nodes and Lymphatic Vessels During Lymphatic Mapping

• Dissolve SPY AGENT GREEN with 20 mL Sterile Water for Injection, USP to form a concentration of 1.25 mg indocyanine green/mL.

SPY AGENT GREEN (indocyanine green for injection, USP) is a sterile lyophilized green powder containing 25 mg of indocyanine green with no more than 5% sodium iodide provided in a 20 mL single-patient use vial.

SPY AGENT GREEN is contraindicated in patients with a history of hypersensitivity to indocyanine green. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)] .

Hypersensitivity reactions including anaphylaxis, urticaria, and deaths due to anaphylaxis have been reported following intravenous administration of indocyanine green. [see Adverse Reactions (6)]. Always have cardiopulmonary resuscitation personnel and equipment readily available and monitor all patients for hypersensitivity reactions.

Because SPY AGENT GREEN contains iodine, 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 a week following administration of SPY AGENT GREEN [see Drug Interactions (7)].

The following adverse reactions are discussed in greater detail in other sections of the label:

• 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.

Effect on Radioactive Iodine Uptake Studies
Because SPY AGENT GREEN contains iodine, 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 SPY AGENT GREEN [see Warnings and Precautions (5.2)].

Risk Summary
There are no adequate and well-controlled studies of SPY AGENT 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.

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 SPY AGENT GREEN and any potential adverse effects on the breastfed infant from SPY AGENT GREEN or from the underlying maternal condition.

Use of indocyanine green for visualization of vessels, blood flow and tissue perfusion has been established in pediatric patients one 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 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 less than one month of age.

Use of indocyanine green for visualization of extrahepatic biliary ducts has been established in pediatric patients aged 12 to 17 years. 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 less 12 years of age.

The safety and efficacy of indocyanine green for visualization of lymph nodes and lymphatic vessels during lymphatic mapping for cervical and uterine tumors has not been established in pediatric patients.

Of the total number of subjects in clinical studies of SPY AGENT GREEN in visualization of vessels, blood flow, and tissue perfusion, 7 percent were 65 and over, while 1 percent were 75 and over and of the total number of subjects in clinical studies of SPY AGENT GREEN in visualization of lymph nodes and lymphatic vessels during lymphatic mapping, 9 percent were 65 and over, while 2 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Clinical studies of SPY AGENT GREEN in visualization of extrahepatic biliary ducts did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the 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.

SPY AGENT GREEN (indocyanine green for injection, USP) is a water soluble, optical imaging agent which is reconstituted with Sterile Water for Injection, USP, for intravenous or interstitial use. Each vial contains a sterile, lyophilized green powder containing 25 mg of indocyanine green with not more than 5% sodium iodide. Hydrochloric acid or sodium hydroxide may be used to adjust the pH prior to lyophilization.

The chemical name for Indocyanine Green is 1 HBenz[e]indolium, 2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e] indol-2-ylidene]-1,3,5-heptatrienyl]-1,1-dimethyl-3-(4-sulfobutyl)-, hydroxide, inner salt, sodium salt.

Molecular Formula: C ₄₃H ₄₇N ₂NaO ₆S ₂; Molecular Mass: 774.96 g/mol, with the following structural formula:

Chemical Structure (Spy Agent Green 01)

Indocyanine green has a peak spectral absorption at 800 nm. SPY AGENT GREEN has a pH of 5.5 to 7.5 when reconstituted with Sterile Water for Injection, USP.

When bound to proteins in plasma or in lymph fluid, indocyanine green absorbs light in the near-infrared region 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 ICG to absorb, resulting in excitation of the ICG 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.

There is no relevant pharmacodynamic data.

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 is taken up by the lymphatic vessels and lymph nodes.

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

The plasma fractional disappearance rate at a 0.5 mg/kg dose has been reported to be significantly greater in women than in men, although there was no significant difference in the calculated value for clearance.

Visualization of Lymph Nodes and Lymphatic Vessels During Lymphatic Mapping of Cervical and Uterine Tumors

FILM Study (NCT 02209532)
FILM was a randomized, prospective, multi-center, open-label study in patients with early stage uterine or cervical cancers and no known regional nodal or metastatic disease by standard clinical evaluation. SPY AGENT 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 SPY AGENT GREEN followed by blue dye or blue dye followed by SPY AGENT GREEN. A total of four 1 mL injections of a 1.25 mg/mL solution of SPY AGENT GREEN were administered into the cervix at the 3 and 9 o’clock positions with a superficial (1 to 3 mm) and a deep (1 to 3 cm) injection at each position for a total dose of 5 mg per patient. Lymphatic mapping was performed intraoperatively using the PINPOINT^® Fluorescence Imaging System and standard light, followed by excision of tissues identified by SPY AGENT 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 SPY AGENT GREEN and the PINPOINT^® Fluorescence Imaging System 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 SPY AGENT GREEN and/or the blue dye comparator.

Table 1 shows the distribution of resected, confirmed lymph nodes by the presence or absence of SPY AGENT GREEN or blue dye in the modified intent-to-treat population (mITT). Among the confirmed lymph nodes identified, 93% were identified using SPY AGENT 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 SPY AGENT GREEN or blue dye. With SPY AGENT 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].

NDC 66259-146-01
SPY AGENT GREEN (indocyanine green for injection, USP) is supplied as 25 mg of lyophilized powder in a 20 mL single patient use vial in the following configurations:

NDC 63323-185-10 (or NDC 0409-4887-10) Sterile Water for Injection, USP, 10 mL fill in 10 mL plastic vials.

Hypersensitivity Reactions

Advise patients to seek medical attention for reactions following injection of SPY AGENT GREEN such as difficulty breathing, swollen tongue or throat, skin reactions including hives, itching and flushed or pale skin, low blood pressure, a weak and rapid pulse and other symptoms or signs of an anaphylactic reaction [see Warnings and Precautions (5.1)].

Manufactured by:
Patheon Italia S.p.A.
Ferentino (FR), Italy

Distributed by:
Novadaq Technologies ULC
8329 Eastlake Drive, Unit 101,
Burnaby, BC, Canada V5A 4W2

Sterile Water for Injection, USP is manufactured by:
Fresenius Kabi USA, LLC
Grand Island, NY 14072 U.S.A.
or
Hospira, Inc.
Rocky Mount, NC 27804 U.S.A.

LB0016-03