Indocyanine Green

ZYOGREEN 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 ( 1.1 ) Fluorescence imaging of extrahepatic biliary ducts in adults and pediatric patients from birth to less than 1 year of age and 6 years of age 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 ZYOGREEN 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.

1.2 Visualization of Extrahepatic Biliary Ducts ZYOGREEN is indicated for fluorescence imaging of extrahepatic biliary ducts in adults and pediatric patients from birth to less than 1 year of age and 6 years of age and older.

1.3 Lymphatic Mapping of Cervical and Uterine Cancer ZYOGREEN 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 ZYOGREEN is indicated for use in ophthalmic angiography in adults and pediatric patients.

Injection: 25 mg per 10 mL (2.5 mg per mL) of indocyanine green as a deep emerald-green ready-to-use solution in a single-dose ampule. Injection: 25 mg per 10 mL (2.5 mg per mL) of indocyanine green as a ready-to-use solution in a single-dose ampule ( 3 )

ZYOGREEN 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 )

Hypersensitivity reactions: Always have cardiopulmonary resuscitation personnel and equipment readily available and monitor patients. ( 5.1 )

5.1 Hypersensitivity Reactions Hypersensitivity reactions including anaphylaxis, urticaria, and deaths due to anaphylaxis have been reported following intravenous administration of indocyanine green, the active ingredient in ZYOGREEN [see Adverse Reactions ( 6 )]. ZYOGREEN 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 ZYOGREEN contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration [see Drug Interactions ( 7 )].

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, the active ingredient in ZYOGREEN. 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 Sagent Pharmaceuticals at 1–800-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of ZYOGREEN 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 ZYOGREEN and any potential adverse effects on the breastfed infant from ZYOGREEN or from the underlying maternal condition.

8.4 Pediatric Use Use in Pediatric Patients for Visualization of Vessels, Blood Flow and Tissue Perfusion The safety and effectiveness of ZYOGREEN 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 have been established in pediatric patients. Use of ZYOGREEN for this indication in pediatric patients is supported by evidence from clinical trials in adults and published studies that demonstrated the utility of indocyanine green for blood vessel evaluation and assessment of tissue perfusion in 59 pediatric patients, including 6 neonates, during surgeries within the indicated surgical categories. Use in Pediatric Patients for Visualization of Extrahepatic Biliary Ducts The safety and effectiveness of ZYOGREEN for fluorescence imaging of extrahepatic biliary ducts have been established in pediatric patients from birth to less than 1 year of age and in those 6 years of age and older. Use of ZYOGREEN for this indication in these age groups is supported by evidence from clinical trials in adults and from the following published studies in pediatric patients. For patients less than 1 year of age, supporting publications included two prospective observational studies and one retrospective case series evaluating a total of 34 pediatric patients (age range: 2 to 119 days) with jaundice undergoing Kasai portoenterostomy who received indocyanine green for fluorescence imaging of biliary structures. For patients 6 years of age and older, a supporting publication consisted of a prospective, single institution case series in 31 pediatric patients (age range: 6 to 18 years) undergoing cholangiography with indocyanine green during laparoscopic cholecystectomy. The safety and effectiveness of ZYOGREEN have not been established for fluorescence imaging of extrahepatic biliary ducts in pediatric patients 1 year to less than 6 years of age. Use in Pediatric Patients for Ophthalmic Angiography ZYOGREEN is indicated for ophthalmic angiography in pediatric patients. Use in Pediatric Patients for Lymphatic Mapping of Cervical and Uterine Cancer The safety and effectiveness of ZYOGREEN for fluorescence imaging of lymph nodes and lymphatic vessels during lymphatic mapping for cervical and uterine cancer have not been established in pediatric patients.

8.5 Geriatric Use Of the total number of subjects 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 subjects 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. 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 elderly and younger patients. Clinical studies of indocyanine green for 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. 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.

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.